MHC-presentable peptides associated with type 1 diabetes

Abstract

Provided herein are MHC-presentable peptides associated with Type 1 diabetes. Also provided are antigen-presenting cells presenting such MHC-presentable peptides, T cells reactive to such MHC-presentable peptides, and related compositions and therapies.

Description

MHC-PRESENTABLE PEPTIDES ASSOCIATED WITH TYPE 1 DIABETES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Nos. 63 / 587,028, filed on September 29, 2023, and 63 / 619,403, filed on January 10, 2024, the disclosures of which are incorporated herein by reference in their entireties. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted sequence listing (Name: 4985_041PC02_SequenceListing_ST26.xml; Size: 351,096 bytes; and Date of Creation: September 27, 2024) is herein incorporated by reference in its entirety. FIELD OF THE DISCLOSURE

[0003] The disclosure relates to MHC-presentable peptides associated with Type 1 Diabetes (T1D). The disclosure also relates to antigen-presenting cells (APCs) presenting such MHC- presentable peptides, T cells reactive to such MHC-presentable peptides, and related compositions and therapies. BACKGROUND

[0004] Type 1 Diabetes (T1D) is a prevalent chronic disease with about 1.6 million adult and pediatric patients in the United States, and about 64,000 new cases diagnosed per year. T1D is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic β cells, resulting in a deficiency of insulin synthesis and secretion. To manage the disease, patients are dependent on insulin substitution therapy for the rest of their lives. To date, there is no cure for T1D. The standard of care treatment for T1D includes administration of insulin, metformin, Pramlintide (SYMLIN®), blood pressure drugs, cholesterol medications, and aspirin, as well as exercise and diet. The first and only disease modifying drug for T1D was FDA approved in 2022 for the delay of T1D, TZIELDTM, no other disease modifying therapy is approved for T1D.

[0005] Despite advances in treatment modalities for T1D patients, the majority of T1D patients have a lower life expectancy and are at a chronic risk for diabetic coma or ketoacidosis. Long term T1D damages the heart and blood vessels, mainly by promoting high blood pressure and atherosclerosis that can lead to other diabetes-related complications, such as heart disease, chronickidney disease, nerve damage, and other problems with feet, oral health, vision, hearing, and mental health. Accordingly, there remains a need for new treatments for these patients. SUMMARY OF THE DISCLOSURE

[0006] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in Table 1A, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

[0007] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in Table 2A, Table 2B, or Table 3, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

[0008] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 6. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth inSEQ ID NO: 6 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO: 9.

[0009] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 10 SEQ ID NO: 11, or SEQ ID NO: 12, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 10. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 10 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 13.

[0010] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16, or (ii) the amino acid sequence comprising theMHC-presentable peptide which comprises, consists essentially of, or consists of the least 8 amino acids of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 14. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 14 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 17.

[0011] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the composition for use the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 18. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 18 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consistsessentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 21.

[0012] In some aspects, the present disclosure provides, a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 22. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 22 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 25.

[0013] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

[0014] In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, atleast 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 26. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 26 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC- presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 29.

[0015] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 30. In some aspects, the MHC-presentable peptide sequence set forth in SEQ ID NO: 30 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 33.

[0016] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptidewhich comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 34. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 34 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 37.

[0017] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of sequence at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 38. In some aspects, the MHC-presentable peptide sequence set forth in SEQ ID NO: 38 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight aminoacids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 41.

[0018] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 42. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 42 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 45.

[0019] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 aminoacids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 46. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 46 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 49.

[0020] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 50, SEQ ID NO: 51, or SEQ ID NO: 52, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 50. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 50 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 53.

[0021] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptidewhich comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 54. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 54 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 57.

[0022] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 58. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 58 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four aminoacids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 61.

[0023] In some aspects, the present disclosure provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 62, SEQ ID NO: 63, or SEQ ID NO: 64, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 62. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 62 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 65.

[0024] In some aspects, the MHC-presentable peptide in the amino acid sequence is less than 35 amino acids, less than 34 amino acids, less than 33 amino acids, less than 32 amino acids, less than 31 amino acids, less than 30 amino acids, less than 29 amino acids, less than 28 amino acids, less than 27 amino acids, less than 26 amino acids, less than 25 amino acids, less than 24 amino acids, less than 23 amino acids, less than 22 amino acids, less than 21 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, less than 12 amino acids, less than 11 amino acids, less than 10 amino acids, or less than 9 amino acids. In some aspects the MHC-presentable peptide in the amino acid sequence consists of 9 aminoacids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 amino acids, or 35 amino acids. In some aspects, the MHC-presentable peptide in the amino acid sequence has 8-35 amino acids, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 8-34, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 8-33, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15- 33, 8-32, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 8-31, 9-31, 10-31, 11-31, 12-31, 13-31, 14-31, or 15-31 amino acids. In some aspects, the amino acid sequence further comprises a second MHC-presentable peptide that is heterologous to the MHC-presentable peptide. In some aspects, the amino acid sequence further comprises a third MHC-presentable peptide, a fourth MHC- presentable peptide, a fifth MHC-presentable peptide, a sixth MHC-presentable peptide, a seventh MHC-presentable peptide, a ninth MHC-presentable peptide, a tenth MHC-presentable peptide, an 11th MHC-presentable peptide, a 12th MHC-presentable peptide, a 13th MHC-presentable peptide, a 14th MHC-presentable peptide, a 15th MHC-presentable peptide, a 16th MHC- presentable peptide, a 17th MHC-presentable peptide, an 18th MHC-presentable peptide, a 19th MHC-presentable peptide, a 20th MHC-presentable peptide, a 21st MHC-presentable peptide, a 22nd MHC-presentable peptide a 23rd MHC-presentable peptide, a 24th MHC-presentable peptide, a 25th MHC-presentable peptide, a 26th MHC-presentable peptide, a 27th MHC- presentable peptide, a 28th MHC-presentable peptide, a 29th MHC-presentable peptide, a 30th MHC-presentable peptide, a 31st MHC-presentable peptide, a 32nd MHC-presentable peptide, a 33rd MHC-presentable peptide, a 34th MHC-presentable peptide, a 35th MHC-presentable peptide, a 36th MHC-presentable peptide, a 37th MHC-presentable peptide, a 38th MHC- presentable peptide, a 39th MHC-presentable peptide, a 40th MHC-presentable peptide, a 41st MHC-presentable peptide, a 42nd MHC-presentable peptide, a 43rd MHC-presentable peptide, a 44th MHC-presentable peptide, a 45th MHC-presentable peptide, a 46th MHC-presentable peptide, a 47th MHC-presentable peptide, a 48th MHC-presentable peptide, a 49th MHC- presentable peptide, a 50th MHC-presentable peptide, a 51st MHC-presentable peptide, a 52nd MHC-presentable peptide, a 53rd MHC-presentable peptide, a 54th MHC-presentable peptide, or a 55th MHC-presentable peptide.

[0025] In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ IDNO: 42, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: 58, or SEQ ID NO: 62. In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, or SEQ ID NO: 65. In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 60, or SEQ ID NO: 66. In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, or SEQ ID NO: 67. In some aspects, the MHC- presentable peptide is specific to HLA-DQ2.5 and / or HLA-DQ8. In some aspects, the MHC- presentable peptide is specific to HLA-DQ2.5. In some aspects, the MHC-presentable peptide is specific to HLA-DQ8.

[0026] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in Table 1A, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in Table 2A, Table 2B, or Table 3, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentablepeptide sequence as set forth SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 6. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 6 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO: 9.

[0027] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 10, SEQ ID NO: 11, or SEQ ID NO: 12, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 10. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 10 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects,the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 13.

[0028] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the least 8 amino acids of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 14. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 14 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 17.

[0029] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 18. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth inSEQ ID NO: 18 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 21.

[0030] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 22. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 22 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 25.

[0031] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentablepeptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 26. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 26 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 29.

[0032] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 30. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 30 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 33.

[0033] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptidewhich comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 34. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 34 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 37.

[0034] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of sequence at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 38. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 38 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids,or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 41.

[0035] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 42. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 42 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 45.

[0036] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 46. In some aspects, the MHC-presentablepeptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 46 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 49.

[0037] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 50, SEQ ID NO: 51, or SEQ ID NO: 52, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 50. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 50 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 53.

[0038] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 aminoacids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 54. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 54 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 57.

[0039] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 58. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 58 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 61.

[0040] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 62, SEQ ID NO: 63, or SEQ ID NO: 64, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 62. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 62 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 65.

[0041] In some aspects, the MHC-presentable peptide in the amino acid sequence is less than 35 amino acids, less than 34 amino acids, less than 33 amino acids, less than 32 amino acids, less than 31 amino acids, less than 30 amino acids, less than 29 amino acids, less than 28 amino acids, less than 27 amino acids, less than 26 amino acids, less than 25 amino acids, less than 24 amino acids, less than 23 amino acids, less than 22 amino acids, less than 21 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, less than 12 amino acids, less than 11 amino acids, less than 10 amino acids, or less than 9 amino acids. In some aspects, the MHC-presentable peptide in the amino acid sequence consists of 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 amino acids, or 35 amino acids. In some aspects, the MHC-presentable peptide in theamino acid sequence has 8-35 amino acids, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 8-34, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 8-33, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15- 33, 8-32, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 8-31, 9-31, 10-31, 11-31, 12-31, 13-31, 14-31, or 15-31 amino acids. In some aspects, the MHC-presentable peptide amino acid sequence further comprises a second MHC-presentable peptide that is heterologous to the MHC-presentable peptide. In some aspects, the amino acid sequence further comprises a third MHC-presentable peptide, a fourth MHC-presentable peptide, a fifth MHC-presentable peptide, a sixth MHC- presentable peptide, a seventh MHC-presentable peptide, a ninth MHC-presentable peptide, a tenth MHC-presentable peptide, an 11th MHC-presentable peptide, a 12th MHC-presentable peptide, a 13th MHC-presentable peptide, a 14th MHC-presentable peptide, a 15th MHC-presentable peptide, a 16th MHC-presentable peptide, a 17th MHC-presentable peptide, an 18th MHC- presentable peptide, a 19th MHC-presentable peptide, a 20th MHC-presentable peptide, a 21st MHC-presentable peptide, a 22nd MHC-presentable peptide a 23rd MHC-presentable peptide, a 24th MHC-presentable peptide, a 25th MHC-presentable peptide, a 26th MHC-presentable peptide, a 27th MHC-presentable peptide, a 28th MHC-presentable peptide, a 29th MHC- presentable peptide, a 30th MHC-presentable peptide, a 31st MHC-presentable peptide, a 32nd MHC-presentable peptide, a 33rd MHC-presentable peptide, a 34th MHC-presentable peptide, a 35th MHC-presentable peptide, a 36th MHC-presentable peptide, a 37th MHC-presentable peptide, a 38th MHC-presentable peptide, a 39th MHC-presentable peptide, a 40th MHC- presentable peptide, a 41st MHC-presentable peptide, a 42nd MHC-presentable peptide, a 43rd MHC-presentable peptide, a 44th MHC-presentable peptide, a 45th MHC-presentable peptide, a 46th MHC-presentable peptide, a 47th MHC-presentable peptide, a 48th MHC-presentable peptide, a 49th MHC-presentable peptide, a 50th MHC-presentable peptide, a 51st MHC- presentable peptide, a 52nd MHC-presentable peptide, a 53rd MHC-presentable peptide, a 54th MHC-presentable peptide, or a 55th MHC-presentable peptide.

[0042] In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: 58, or SEQ ID NO: 62. In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, or SEQ ID NO: 65.In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 60, or SEQ ID NO: 66. In some aspects, the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, or SEQ ID NO: 67.

[0043] In some aspects, the MHC-presentable peptide is specific to HLA-DQ2.5 and / or HLA- DQ8. In some aspects, the amino acid sequence induces a tolerizing immune response. In some aspects, the tolerizing immune response is against Type 1 Diabetes. In some aspects, the immune response comprises (i) an induction of antigen-specific T cell tolerance, (ii) an increase in Treg cells (e.g., CD4+ Treg cells or FOXP3+ Treg cells), (iii) inhibition of autoimmunity, (iv) an induction of anergy of effector T cells, (e.g., CD4+ T effector cells), (v) inhibition of cytokine production, (vi) a decrease in a pro-inflammatory cytokine, (vii) an increase in an immunosuppressive cytokine, (viii) a suppression of CD8+ effector cells, (ix) an increase of LAG3+ CD49b+ Tr1 cells, or any combination thereof. In some aspects, the immune response comprises an increase in the number of Treg cells, e.g., FOXP3+ Treg cells. In some aspects, the immune response comprises an increase of Type 1 Regulatory (Tr1) cells. In some aspects, the immune response comprises a decrease of a pro-inflammatory cytokine, wherein the pro- inflammatory cytokine comprises Interferon-γ, Interleukin-1, Interleukin-2, Interleukin-12, Interleukin-16, Interleukin-17, Interleukin-18, Interleukin-21, Interleukin-22, Interleukin-23, Tumor Necrosis Factor-α, or any combination thereof. In some aspects, the immune response comprises an increase of an immunosupressive cytokine, wherein the immunosuppressive cytokine comprises Interleukin-1R α, Interleukin-4, Interleukin-10, Interleukin-11, Interleukin-13, Tumor Growth Factor-β, Interleukin-33, Interleukin-35, Interleukin-37, or any combination thereof. In some aspects, at least one MHC-presentable peptide is derived from a protein comprising Chromogranin-A (CHGA), Carboxypeptidase A1(CPA1), C1orf127 protein (C1orf127), Early growth response protein 4 (EGR4), Glutamate decarboxylase 2 (GAD2), Vitamin D-binding protein (GC), Guanine nucleotide-binding protein G(s) subunit alpha isoform XLas (GNAS), Glucose-6-phosphatase 2 (G6PC2 (IGRP)), Insulin (INS), Potassium channel subfamily K member 16 (KCNK16), Kinesin-like protein KIF1A (KIF1A), Neuroendocrine convertase 2 (PCSK2), Pancreas / duodenum homeobox protein 1 (PDX1), Proton-coupled zinc antiporter SLC30A8(SLC30A8), or any combination thereof. In some aspects, the nucleotide sequence comprises an RNA, DNA, or any combination thereof. In some aspects, the nucleotide sequence comprises an mRNA.

[0044] In some aspects, one or more of the MHC-presentable peptides are an MHC class II peptide. In some aspects, all of the MHC-presentable peptides are MHC class II peptides. In some aspects, one or more of the MHC-presentable peptides are an MHC class I peptide. In some aspects, two or more MHC-presentable peptides are a combination of an MHC class I peptide and an MHC class II peptide.

[0045] In some aspects, the nucleotide sequence comprises a single open reading frame that encodes one or more MHC-presentable peptides. In some aspects, the single open reading frame encodes all MHC-presentable peptides in the amino acid sequence. In some aspects, the nucleotide sequence comprises one or more open reading frames that encode one or more MHC-presentable peptides. In some aspects, the nucleotide sequence comprises a plurality of open reading frames that encodes one or more MHC-presentable peptides. In some aspects, the amino acid sequence encoded by the nucleotide sequence further comprises MHC-presentable peptides directly linked to each other without a linker. In some aspects, the amino acid sequence comprising the MHC- presentable peptides further comprises a linker between two MHC-presentable peptides. In some aspects, the linker comprises a single amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids. In some aspects, the linker comprises a flexible linker. In some aspects, the linker comprises a cleavable linker. In some aspects, the linker comprises an amino acid sequence selected from the group consisting of the linkers set forth in Table 4. In some aspects, two or more of the MHC-presentable peptides comprise amino acid sequences of different lengths. In some aspects, one or more of the MHC-presentable peptides comprises a flank region at the N terminus (N terminus flank) and / or the C terminus (C terminus flank) of the MHC-presentable peptides. In some aspects, the total length of the amino acid sequence comprises 50-100 amino acids, 100-200 amino acids, 200-300 amino acids, 300-400 amino acids, 400-500 amino acids, 500-600 amino acids, 600-700 amino acids, 700-800 amino acids, 800-900 amino acids, 900-1000 amino acids, 1000-1100 amino acids, or 1100-1200 amino acids. In some aspects, the nucleotide sequence further comprises a 5’ UTR. In some aspects, the nucleotide sequence further comprises a 3’ UTR. In some aspects, the nucleotide sequence further comprises a poly-A tail. In some aspects, the nucleotide sequence further comprises a cap structure. In some aspects, the cap structure comprises a 5' cap structure, a 5' cap-0 structure, a 5' cap-l structure, or a 5' cap-2 structure. In some aspects,the nucleotide sequence comprises a nucleic acid having at least one chemical modification. In some aspects, the chemical modification is in the nucleic acid base, in the nucleic acid sugar, or in the nucleic acid backbone. In some aspects, the chemical modification in the base comprises pseudouridine, Nl-methylpseudouridine, Nl-ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5- methylcytosine, 2-thio-l-methyl-l-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5- aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4- methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-l -methyl-pseudouridine, 4-thio- pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methyluridine, 5- methoxyuridine, or 2'-0-methyl uridine. In some aspects, the chemical modification in the sugar comprises Locked Nucleic Acid (LNA); 2'-O-alkyl-RNA; 2'-amino-DNA; 2'-fluoro-DNA; arabino nucleic acid (ANA); 2'-fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), constrained ethyl nucleic acid (cEt), 2'-O-methyl nucleic acid (2'-OMe), or 2'-O-methoxyethyl nucleic acid (2'-MOE). In some aspects, the chemical modifications in the backbone comprises a phosphorodiamidate morpholino oligomer (PMO) and / or phosphorothioate (PS) modification. In some aspects, the MHC-presentable peptides are encoded by a nucleotide sequence. In some aspects, all the MHC-presentable peptides are encoded by a single nucleotide sequence. In some aspects, all the MHC-presentable peptides are encoded by at least two heterologous nucleotide sequences.

[0046] In some aspects, all of the MHC-presentable peptides are derived from one or more Type 1 Diabetes (T1D) antigens. In some aspects, one or more of the MHC-presentable peptides are derived from an antigen specific to a subject having Type 1 Diabetes (“subject specific T1D antigen”). In some aspects, one or more of the MHC-presentable peptides are immunogenic.

[0047] In some aspects, the nucleotide sequence or the amino acid sequence is delivered by a delivery agent. In some aspects, the delivery agent is capable of delivering the nucleotide sequence or the amino acid sequence to a target cell. In some aspects, the delivery agent comprises a liposome, a lipid nanoparticle, an exosome, a lipid-like particle, a lipoplex, a microvesicle, a vector, or any combination thereof. In some aspects, the delivery agent comprises a nanoparticle. In some aspects, the target cell is a pancreatic cell, a dendritic cell, a macrophage, a B cell, or a non- professional antigen presenting cell. In some aspects, the target cell is a tolerogenic cell. In some aspects, the tolerogenic cell is a cell in the liver, optionally selected from a liver sinusoidal endothelial cell, a MARCO+ Kupffer cell, and a monocyte-derived macrophage. In some aspects, the tolerogenic cell is a cell in the spleen, optionally selected from a marginal zone macrophage, a metallophilic macrophage, and a marginal zone dendritic cell. In some aspects, the target cell is apancreatic cell. In some aspects, the delivery agent has a negative zeta potential. In some aspects, the delivery agent comprises a ligand that binds the target cell.

[0048] In some aspects, the present disclosure provides an MHC complex comprising an MHC class I or II molecule and an MHC-presentable peptide comprising at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in Table 1A. In some aspects, the present disclosure provides an MHC complex comprising an MHC class I or II molecule and an MHC-presentable peptide encoded by the nucleotide sequence in the composition. In some aspects, MHC complex comprises an MHC class I molecule only, an MHC class II molecule only, or both an MHC class I molecule and an MHC class II molecule.

[0049] In some aspects, the present disclosure provides, an antigen presenting cell (APC) comprising the MHC complex. In some aspects, the present disclosure provides a pharmaceutical composition comprising the composition, the MHC complex, or the antigen presenting cell, and a pharmaceutically acceptable excipient.

[0050] In some aspects, the composition for use further comprising administering an immunomodulator. In some aspects, the composition further comprises an immunomodulator. In some aspects, the immunomodulator is encoded by a nucleotide sequence. In some aspects, the immunomodulator is encoded by the same nucleotide sequence that encodes the MHC-presentable peptides. In some aspects, the immunomodulator comprises an immunomodulatory cytokine or a nucleic acid encoding the immunomodulatory cytokine. In some aspects, the immunomodulatory cytokine comprises IL-2, IL-10, TGF-β, IL-37, IL-27, IL-35, CXCL11, CCL17, OX40L / Jagged- 1, Vasoactive Intestinal MHC-presentable peptide (VIP), or any combination thereof. In some aspects, the immunomodulatory cytokine comprises an IL-2 protein that preferentially activates the IL-2Rαβγ receptor complex relative to the IL-2Rβγ receptor complex. In some aspects, the immunomodulatory cytokine comprises an IL-10 protein. In some aspects, the immunomodulatory cytokine comprises a TGF-β protein. In some aspects, the immunomodulator comprises or further comprises a nucleic acid encoding an intracellular or transmembrane immunomodulatory protein. In some aspects, the intracellular or transmembrane immunomodulatory protein comprises PD-L1, PD-L2, ICOS ligand, ILT3, ILT4, BTLA, Fas, CD39, indoleamine 2,3-dioxygenase 1 (IDO1), CHUK, Ikkb, GILZ, or any combination thereof. In some aspects, the immunomodulator comprises an immunomodulatory compound. In some aspects, the immunomodulatory compound comprises vitamin A, vitamin D, adenosine, kynurenine, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatirameracetate, mitoxantrone, natalizumab, or any combination thereof. In some aspects, the immunomodulator is in or on the delivery agent.

[0051] In some aspects, the present disclosure provides a kit comprising the composition for use, the composition, the MHC complex, the antigen presenting cell, or the pharmaceutical composition, and instructions for use.

[0052] In some aspects, the present disclosure provides a method of increasing CD4+ Treg cells in a subject in need thereof comprising administering the composition or the pharmaceutical composition to the subject. In some aspects, the present disclosure provides a method of decreasing CD8+ Treg cells in a subject in need thereof comprising administering the composition or the pharmaceutical composition to the subject. In some aspects, the present disclosure provides a method of increasing Type 1 Regulatory (Tr1) cells or inducing T-regulatory 35 (iTr35) cells in a subject in need thereof comprising administering the or the pharmaceutical composition to the subject. In some aspects, the present disclosure provides a method of increasing LAG3+CD49b+ Tr1 cells in a subject in need thereof comprising administering the composition or the pharmaceutical composition to the subject. In some aspects, the present disclosure provides a method of inducing an anergy of T effector cells in a subject in need thereof comprising administering the composition or the pharmaceutical composition to the subject. In some aspects, the present disclosure provides a method of inducing an anergy of CD4+ T effector cells in a subject in need thereof comprising administering the composition or the pharmaceutical composition to the subject. In some aspects, the present disclosure provides a method of producing the composition, the MHC complex, the antigen presenting, or the pharmaceutical composition, comprising adding a nucleotide sequence encoding the MHC-presentable peptide in the nucleotide sequence. In some aspects, the present disclosure provides a method of inducing a tolerizing immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition, the MHC complex, the antigen presenting cell, or the pharmaceutical composition. In some aspects, the present disclosure provides a method of inducing a T cell response against Type 1 Diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition, the MHC complex, the antigen presenting cell, or the pharmaceutical composition. In some aspects, the present disclosure provides a method of preventing or treating Type 1 Diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition, the MHC complex, the antigen presenting cell, or the pharmaceutical composition.

[0053] In some aspects, the present disclosure provides a use of the composition, the MHC complex, the antigen presenting cell, or the pharmaceutical composition in the manufacture of a medicament for inducing a tolerizing immune response against Type 1 Diabetes. In some aspects, the present disclosure provides a use of the composition, the MHC complex, the antigen presenting cell, or the pharmaceutical composition for use in the manufacture of a medicament for treating or preventing Type 1 Diabetes.

[0054] In some aspects, the composition, the MHC complex, the antigen presenting cell, the pharmaceutical composition, or the medicament is administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly, intracardiacly, intradermally, intraperitoneally, intrathecally, or transdermally.

[0055] In some aspects, the present disclosure provides a means for inducing a tolerogenic immune response in a subject in need thereof, in combination with a pharmaceutically acceptable carrier. In some aspects, the present disclosure provides a method of treating or preventing type I diabetes in a subject in need thereof comprising administering to the subject a means for inducing a tolerogenic immune response in combination with a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE FIGURES

[0056] FIG. 1 shows a schematic diagram of an exemplary mRNA construct (a string polynucleotide sequence) that expresses multiple MHC-presentable peptides when translated.

[0057] FIG.2 shows a schematic diagram of an exemplary epitope cassette to be included in a mRNA construct, such as the construct shown in FIG.1.

[0058] FIG.3 shows an exemplary plot demonstrating peptide presentation by MHC molecules identified by MEDi.

[0059] FIG.4 shows exemplary linker sequences as Table 4.

[0060] FIGs.5A-5B show the in vivo efficacy of an mRNA tolerizing vaccine in a Nonobese Diabetic (NOD) mouse model of Type 1 Diabetes. FIG. 5A provides the blood glucose levels (mg / dL) in the mice following administration of a Lipid Particle Formulation containing KIF1a mRNA and tol105 mRNA (tolerizing mRNA). FIG.5B provides the percent normal glucose in the NOD mice following administration of the Lipid Particle Formulation containing KIF1a mRNA and tol105 mRNA (tolerizing mRNA).

[0061] FIG.6A-6B shows exemplary plots showing the NetMHC and immunogenicity scores for tested epitopes. FIG.6A shows the scores for HLA-DQ8 epitopes and FIG.6B shows the scores for HLA-DQ2.5 epitopes.DETAILED DESCRIPTION

[0062] The present disclosure is based, in part, upon the identification of MHC-presentable peptides associated with Type 1 Diabetes (T1D) MHC risk alleles. Some of these MHC- presentable peptides have also been found to induce a robust response from CD4+T cells of individuals carrying T1D-assoicated risk alleles. Accordingly, T1D-associated peptides comprising these MHC-presentable peptides can be used for inducing immune tolerance to cells (e.g., islet β cells) presenting these MHC-presentable peptides. I. DEFINITIONS

[0063] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0064] As used herein, the terms “a” and “an” mean “one or more” and include the plural unless the context is inappropriate.

[0065] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0066] As used herein, the expression “and / or” in connection with two or more recited objects includes individually each of the recited objects and the various combinations of two or more of the recited objects, unless otherwise understood from the context and use. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0067] It is understood that wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of" and / or "consisting essentially of" are also provided. As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0068] As used herein, the terms “antigen-presenting cell” or “APC” refer to a cell or particle that elicits a cellular immune response by displaying a peptide presented by a major histocompatibility complex (MHC) on an outer surface of the cell or particle, for recognition by an immune cell such as a T cell. APCs include, e.g., professional APCs, such as dendritic cells, macrophages, Langerhans cells, and B cells, that express both class I and class II MHCs, and non- professional APCs (e.g., nucleated cells) that generally express only class I MHCs. APCs also include artificial APCs (aAPCs), e.g., cells (e.g., drosophila cells) engineered to express an MHC that presents a peptide. In addition, artificial APCs include particles (e.g., beads, nanoparticles, or liposomes) that present a peptide-MHC on the surface, configured such that the aAPC can prime or stimulate T cells in vitro, ex vivo, or in vivo. Exemplary aAPCs are known in the art and are described in Section V herein.

[0069] As used herein, the term “delivery agent” refers to an agent capable of delivering a cargo (e.g., peptide, protein, nucleic acid, or other compounds) to a target cell, tissue, or organ. In one example, a delivery agent may deliver a cargo into a target cell (e.g., cytosol or endosome of the target cell). In another example, a delivery agent may deliver a cargo to the vicinity of a target cell in a target tissue, such that the cargo can bind to an outer surface of the target cell or be internalized into the target cell. A delivery agent may, e.g., bind to the cargo or encapsulate the cargo. Delivery agents include, for example, particles such as nanoparticles (e.g., lipid nanoparticles), exosomes, lipoplex, lipid-like particles, vectors, microvesicles, or liposomes (e.g., nanoliposomes).

[0070] As used herein, the term “effective amount” refers to the amount of a compound (e.g., a compound of the present disclosure) sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.

[0071] As used herein, percent “identity” between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Similarly, percent “identity” between a nucleic acid sequence and a reference sequence is defined as the percentage of nucleotides in the nucleic acid sequence that are identical to the nucleotides in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent sequence identity (e.g., amino acid sequence identity or nucleic acid sequence identity) can be achieved invarious ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0072] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0073] As used herein, the term “isolated” when used in reference to a biological substance means that the substance is not in its native state or is removed from at least a portion of other molecules associated or occurring with the substance in its native environment (e.g., within a cell or tissue) or in another environment (e.g., in a cell extract, extraction buffer, etc.). An isolated biological substance, e.g., a protein, peptide, nucleic acid, or cell, can be essentially free of other biological molecules. For example, in some aspects, an isolated protein, peptide, nucleic acid, or cell can be at least 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% free of other molecules present in a natural or non-natural environment. For example, in some aspects, an isolated peptide is not present in a native composition of the peptide, e.g., in a cell comprising the peptide in its cytoplasm, or an isolated antigen-presenting cell (“APC”) is not present in a native environment of the APC, e.g., in a biological sample (e.g., tissue or body fluid sample) comprising the APC.

[0074] The term “major histocompatibility complex” or “MHC” refers to a genomic locus containing a group of genes that encode the polymorphic cell‐membrane‐bound glycoproteins known as MHC class I and class II molecules, which regulate the immune response by presenting peptides of fragmented proteins to CD8+(e.g., cytotoxic) and CD4+(e.g., helper) T lymphocytes, respectively. In humans, this group of genes is also called “human leukocyte antigen” or “HLA.” Human MHC class I genes encode, for example, HLA-A, HLA-B, and HLA-C proteins. Class I HLA protein is a heterodimer composed of a heavy α-chain and a smaller β-chain. The α-chain is encoded by a variant HLA gene, and the β chain is an invariant β2 microglobulin (β2m) polypeptide encoded by a separate region of the human genome. Human MHC class II genes encode, for example, HLA-DM, HLA-DO, HLA-DP, HLA-DQ, and HLA-DR proteins. Class II HLA protein is a heterodimer composed of α and β chains both encoded by variant HLA genes. A HLA can include multiple serotypes (e.g., HLA-A*02, HLA-DPA1*02) each of which may include multiplealleles (e.g., HLA-DQ2.5 comprises alleles HLA-DQA1*0501 and DQB1*0201; and HLA-DQ8 comprises DQA1*0301 and DQB1*0302). Nucleotide sequences and a gene map of human MHC are publicly available (e.g., The MHC sequencing consortium, Nature 401:921-923, 1999). The terms “major histocompatibility complex” and “MHC” also refer to the polymorphic glycoproteins encoded by the MHC class I or class II genes, where appropriate in the context, and proteins comprising variants thereof that bind MHC-presentable peptides (e.g., class I or class II peptides). Generally, a class I MHC binds an MHC-presentable peptide in a groove formed by its α1 domain and α2 domain and a class II MHC binds an MHC-presentable peptide in a groove formed by its α1 domain and β1 domain. The term “soluble MHC” refers to an extracellular fragment of an MHC comprising corresponding α1 and α2 domains that bind a class I MHC-presentable peptide or corresponding α1 and β1 domains that bind a class II MHC-presentable peptide, where the α1 and α2 domains or the α1 and β1 domains are derived from a naturally occurring MHC or a variant thereof.

[0075] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier (e.g., a pharmaceutically acceptable carrier), inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0076] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil / water or water / oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Adejare, Remington, The Science and Practice of Pharmacy (23rd Ed. 2020).

[0077] As used herein, the term “presentation agent” refers to an agent (e.g., a cell or particle) that can bind a plurality of peptide-MHC complexes (e.g., a plurality of the same peptide-MHC complexes) for recognition by a TCR, e.g., a TCR expressed by a T cell. Presentation agents include but are not limited to APCs (e.g., dendritic cells or macrophages), artificial APCs (e.g., engineered cells, nanoparticles, or liposomes), and multimerization domains linked to peptide- MHC complexes.

[0078] As used herein, the terms “prime” and “priming,” in the context of antigen-presenting cells and T cells, refers to naïve T cell clonal expansion, activation, and / or generation of memory T cells as a result of TCR engagement by a peptide presented by an MHC on an outer surface of an antigen-presenting cell.

[0079] As used herein, the terms “subject” and “patient” are used interchangeably and refer to an organism to be treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably include humans.

[0080] As used herein, the term “target cell” refers to a cell that can be targeted by a delivery agent. For example, a target cell may have a cell surface receptor (e.g., a TCR) that can be bound by the delivery agent, e.g., via a ligand present on the delivery agent that binds the cell surface receptor. In another example, a target cell may be located in a specific tissue or organ (e.g., liver, lymph nodes, or spleen) that the delivery agent is enriched in or delivered to. A target cell may comprise, e.g., an immune cell (e.g., dendritic cell or macrophage).

[0081] As used herein, a cell composition is “substantially free” of a specified type of cells if this type of cells does not exceed 0.1%, 0.01%, or 0.001% of the total amount of cells in the composition. The percentage of each cell type in a cell composition can be determined using a method known in the art. For example, immune cells are often characterized by cell type-specific markers (e.g., cell surface markers) and the amount of each cell type can be determined by flow cytometry.

[0082] As used herein, the term “MHC-presentable peptide” refers to a peptide of an antigen protein presentable by a class I or class II MHC and do not encompass the full-length antigens or any isoforms thereof. Peptides presentable by class I MHC proteins (e.g., HLA-A, HLA-B) are typically 8-11 amino acids in length. The peptide is located in the peptide-binding groove of the central region of the α1 / α2 domains of the class I MHC. T cell peptides presentable by class II MHC proteins are typically 13-25 amino acids (e.g., 15-24 amino acids) in length. The peptide is located in the peptide-binding groove formed by the α1 / β1 domains of the class II MHC. In addition, the term “MHC-presentable peptide" can be smaller than the peptide sequences disclosed herein, e.g., eight contiguous amino acids, nine contiguous amino acids, ten contiguous amino acids, 11 contiguous amino acids, 12 contiguous amino acids, 13 contiguous amino acids, or 14 contiguous amino acids of a 15mer peptide disclosed herein (e.g., LWVPGAIGSPSQEAV (SEQ ID NO: 6)). In some aspects, the term “MHC-presentable peptide" can refer to a contiguous amino acid sequence that contains the whole length (i.e., 15mer) of a peptide sequence in Table 1A or Table 1B and / or a contiguous amino acid sequence that can be longer than the peptide sequence disclosed in Table 1A or Table 1B. See Table 3 for example. Therefore, the “MHC-presentable peptide" can include additional amino acids that can be processed by antigen processing pathways to be presented on class I and / or class II MHC proteins. Therefore, in some aspects the "MHC-presentable peptide" can include up to 10 additional amino acids at the N terminus and / or up to 10 amino acids at the C terminus of a peptide sequence in Table 1A or Table 1B. For example see Table 3. In some aspects, the additional amino acids are the naturally occurring amino acids flanking a peptide sequence of Table 1A or Table 1B in an antigen sequence described herein. In some aspects, the additional amino acids comprise a spacer sequence. An MHC-presentable peptide is “immunogenic” if the MHC-presentable peptide activates a T cell and / or stimulates a T cell response in a subject, for example, as measured by the amount of total T cells and / or memory T cells, respectively, reactive to the MHC-presentable peptide. The strength and duration of the T cell response (e.g., proliferation or activation) can be specific to the subject’s MHC serotypes and TCR repertoire. Immunogenic MHC-presentable peptides can also be identified in a population of organisms (e.g., humans) with respect to the average strength and duration of T cell response to the peptides.

[0083] As used herein, the terms “T cell receptor” and “TCR” refer to a surface protein (e.g., a heterodimeric protein) of a T cell that allows the T cell to recognize an antigen and / or or a peptide thereof, typically presented by a major histocompatibility complex (MHC) (e.g., an MHC- presentable peptide), or a fragment of such a surface protein comprising at least its variable domains. Typically, TCRs are heterodimers comprising two different protein chains. In many T cells, the TCR comprises an alpha (α) chain and a beta (β) chain. Each chain, in its native form, typically comprises two extracellular domains, a variable (V) domain and a constant (C) domain, the latter of which is membrane-proximal. The variable domain of α-chain (Vα) and the variable domain of β-chain (Vβ) each comprise three hypervariable regions that are also referred to as the complementarity determining regions (CDRs) such as CDR1, CDR2, and CDR3. The CDRs, in particular CDR3, are primarily responsible for contacting MHC-presentable peptides and thus define the specificity of the TCR, although, under certain circumstances, the CDR1 of the α-chain can interact with the N-terminal part of the antigen, and CDR1 of the β-chain interacts with the C- terminal part of the antigen.

[0084] As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. It is understood that T1D can be diagnosed by assessing genetic, immunologic, and / or metabolic markers prior to symptomatic onset. As used herein, the term “treating” also includes prevention of symptomatic onset after observation of the predictive markers.

[0085] As used herein, the term “vehicle” refers to an agent (e.g., delivery agent or presentation agent) that can bind or contain a biomolecule (e.g., a peptide, protein, or nucleic acid). For example, a vehicle can deliver a biomolecule to a target cell, tissue, or organ. In another example, a vehicle can bind one or more peptide-MHC complexes for recognition by a TCR. It is contemplated that in certain aspects, the vehicle that binds or contains the biomolecule is not naturally occurring.

[0086] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls. II. MHC-PRESENTABLE PEPTIDES AND COGNATE MHCS

[0087] T cell-mediated immune responses are generally employed to kill undesired cells, such as cancer cells and pathogen-infected cells. T cells reactive to autoantigens are generally removed by negative selection in the thymus, an organ that shrinks in adulthood. However, failure to remove autoreactive T cells, among other mechanisms, can lead to T cell attack of healthy cells or tissues, resulting in autoimmune diseases (e.g., T1D).

[0088] Unlike humoral immune responses, T cell immunity relies on T cell receptor (TCR) recognition of antigenic peptides presented by MHCs. While only particular MHC-presentable peptides of surface proteins allow targeting by neutralizing antibodies, many peptides can serve as targets of T cells. Peptides from antigens delivered endogenously to APCs (e.g., expressed in the APCs) are processed primarily for association with class I MHC. Peptides from antigens delivered exogenously to APCs (e.g., internalized by endosomes) are processed primarily for association with class II MHC. Thus, T cell immunity can be elicited towards antigen proteins having various physiological functions and localizations.

[0089] Peptides can be presented at different levels on MHC complexes, and this property is referred to herein as "presentability". The presentability of a peptide can be determined by a number of methods comprising Mammalian MHC-presentable peptide Display (MEDi), prediction programs such as NetMHC, Mass Spectrometry, or any combination thereof. peptides (Obermair et al., (2022) Sci. Adv.8, eabl5394)a peptide. In some aspects, a peptide is defined as presentable (i.e., an "MHC-presentable peptide") if the peptide falls in the 50-100% quartile as measured by MEDi.

[0090] In some aspects, MHC-presentable peptides of a given antigen can be identified or selected by in silico methods, for example, as described in Schaap-Johansen et al., (2021) Front. Immunol. 12:712488 or in vitro experimental methods, for example MEDi, as described inObermair et al., (2022) Sci. Adv.8, eabl5394. (see, e.g., WO2019197671). However, these methods generally focus on MHC presentation, whereas the immunogenicity of an MHC-presentable peptide still needs to be determined empirically. Various methods of identifying immunogenic MHC-presentable peptides have been described in the art. For example, a method has been developed to identify immunogenic MHC-presentable peptides from a library of peptide-MHC- TCR fusion (MCR) proteins using human-derived T cell receptors (see Kisielow et al., Nat. Immunol. (2019) 20:652–62; WO2016097334). Each MCR protein includes a peptide, an extracellular domain of an MHC allele, and transmembrane and intracellular domains of a TCR. Reporter T cells are engineered to constitutively express the library of MCR proteins and to express a reporter gene (e.g., GFP) under the control of a TCR-responsive transcription factor (e.g., NFAT). When contacting the reporter T cells and T cells from a patient sample, a reporter T cell expresses the reporter gene if the peptide and MHC of its MCR protein is recognized by a TCR of a patient T cell. By assessing a large number of patient samples, this system can be utilized also for identification of immunongenic MHC-presentable peptides in the library of MCRs that are associated with the disease. For example, this MCR screening platform has identified class I- restricted anti-cancer T cells in HPV positive oropharyngeal cancers (see McInnis et al., (2023) J Immunother Cancer 11:3). Additional methods using autologous APCs pulsed with MHC- presentable peptides of interest can be used to expand rare populations of MHC-presentable peptide-specific T cells, which allows for the identification of immunogenic and immuno prevalence of T cells at higher throughput relative to methods such as MCR. We have demonstrated that both MCR and autologous APC T cell expansion protocols are able to identify disease-relevant T cells, such as T1D-relevant T cells.

[0091] The ability of an MHC-presentable peptide to bind T cells (e.g., T cells of T1D patients) can be assessed using a peptide-MHC multimer (e.g., tetramer) including the MHC-presentable peptide. Such multimers, incorporating the MHC-presentable peptide, a soluble fragment of MHC, and optionally a marker (e.g., fluorophore or barcode), can be produced by various methods in vitro, for example, as described in Jordan et al., J. Immunol. (2008) 180(1): 188–97, WO2021202727; and WO2021262872. Briefly, a T cell sample can be incubated with a library of peptide-MHC (“pMHC”) complex. The T cells that bind the pMHC can then be isolated and the peptides identified. The method can be conducted in a multiplex manner. For example, a plurality of barcoded pMHC multimers can be contacted with T cells in parallel, followed by replicating each TCR-encoding nucleic acid in a hydrogel linked with a barcode (see, e.g., WO2020142724 and WO2021138588). In some aspects, the method of producing an MHC multimer, comprises (a)providing two or more MHC monomers, wherein each monomer comprises a conjugation moiety; (b) providing a multimerization domain, wherein each subunit of the multimerization domain comprises a conjugation moiety; (c) combining the MHC monomers and the multimerization domain under conditions sufficient for covalent conjugation between the MHC monomers and the multimerization domain to produce an MHC multimer. This screening technique allows the determination of immunopravelence as well as cognate MHC-presentable peptide specificity and HLA restriction of a T cell ex vivo.

[0092] In some aspects, an Enzyme-linked immunosorbent spot (ELISpot) assay can be used to test immunogenicity of a peptide. ELISpot quantitatively measures the frequency of cells secreting cytokine out of a population of cells. The ELISpot Assay is also a form of immunostaining since it is classified as a technique that uses antibodies to detect a protein analyte, with the word "analyte" as used herein, referring to any biological or chemical substance being identified or measured.

[0093] In some aspects, the ELISpot assay is a FluoroSpot assay. The FluoroSpot assay is a variation of the ELISpot assay. The FluoroSpot Assay uses fluorescence in order to analyze multiple analytes, meaning it can detect the secretion of more than one type of protein.

[0094] In some aspects, the ELISpot assay comprises the following steps. Cytokine specific monoclonal antibodies are first added to the wells of a plate. Next, the desired cells being observed and analyzed (e.g., T cells) are added to the wells and are subsequently treated with a potentially immune stimulating element (e.g., a candidate peptide), and cytokine secretion is measured. Secreted cytokine from activated cells will bind to antibody adjacent to the activated cell. For analysis, biotinylated cytokine-specific detection antibodies are then added to the well, followed by streptavidin-enzyme conjugation. A substrate is then added to the wells, and is catalyzed by the enzyme conjugate forming an insoluble precipitate in the wells which form spots. The substrate used in this step will depend on the type of enzyme used in the previous step. In some aspects, the streptavidin enzyme substrate combination comprises streptavidin-ALP (streptavidin and alkaline phosphatase conjugate) and BCIP / NBT-plus (a mixture of 5-bromo-4-chloro-3-indolyl phosphate and nitroblue tetrazolium chloride). In some aspects, the streptavidin enzyme substrate combination comprises streptavidin-HRP (streptavidin and horseradish peroxidase conjugate) and TMB (tetramethylbenzidine). The spots are then quantified manually under a microscope or by an automated ELISpot reader to calculate cytokine secretion.

[0095] In some aspects, the assay can detect the production of cytokines IFN-γ, IL-2, TNF- alpha, IL-4, IL-5, and IL-13. The first three cytokines are produced by Th1 cells, while the lastthree are produced by Th2 cells. In some aspects, the production of cytokines as measured by ELISpot suggest the potentially immune stimulating element is immunogenic.

[0096] One of the challenges to developing T cell-directed T1D therapies is identification of strongly immunogenic MHC-presentable peptides that contribute to T1D pathogenesis and the determination of the frequency of T cells reacting to such MHC-presentable peptides. Understanding presentability, immunogenicity, and frequency of T cells reactive to such peptides is critical to selecting MHC-presentable peptides with the most therapeutic potential. Accordingly, the present disclosure provides the MHC-presentable peptides set forth in Table 1A, Table 1B, Table 2A, and / or 2B, and compositions comprising these MHC-presentable peptides, that may be useful in T cell-directed T1D therapies. In some aspects, the MHC presentable peptides are presentable by HLA-DQ and / or HLA-DR serotypes. In some aspects, the MHC-presentable peptides are presentable by known T1D-risk associated HLA serotypes, such as, HLA-DQ2, HLA- DQ8, HLA-DR3, and / or HLA-DR4. In some aspects, the MHC-presentable peptides are presentable by known T1D-risk associated HLA haplotypes, such as, HLA-DQ2.5. In some aspects, the MHC-presentable peptides are presentable by known T1D-risk associated HLA alleles, such as, HLA-DQA1, HLA-DQB1, HLA-DRA1, HLA-DRB1, or any combination thereof. These MHC-presentable peptides can be further characterized by their immunogenicity as determined by functional assays, such as ELISpot, using primary human CD4 T cells derived from donors expressing HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof. Table 1A. Exemplary MHC-presentable Peptides Associated with T1D

[0097] In some aspects, one or more of the MHC-presentable peptide sequences in Table 1A are presentale on T1D-risk associated HLA serotypes, such as, HLA-DQ2, HLA-DQ8, HLA-DR3, and / or HLA-DR4. In some aspects, one or more of the MHC-presentable peptide sequences in Table 1A are presentale on T1D-risk associated HLA serotypes, such as, HLA-DQ2.5, HLA-DQ8, and / or HLA-DRB1 (e.g., HLA-DRB1*0401). In some aspects, the MHC-presentable peptide sequences derived from or comprising any one of SEQ ID NO: 6 to SEQ ID NO: 175 and SEQ ID NO: 213 can be presentable on HLA-DQ8. In some aspects, the MHC-presentable peptide sequences derived from or comprising any one of SEQ ID NO: 131 and SEQ ID NO: 176 to SEQ ID NO: 247 are presentable on HLA-DQ2.5. In some aspects, the MHC-presentable peptide sequences derived from or comprising any one of SEQ ID NO: 83 and SEQ ID NO: 176 are presentable on HLA-DRB1, e.g., HLA DRB1*0401. Table 1B. Exemplary MHC-presentable Peptides Associated with T1D.

[0098] In some aspects, one or more of the MHC-presentable peptide sequences on Table 1B are presentale on T1D-risk associated HLA serotypes, such as, HLA-DQ2, HLA-DQ8, HLA-DR3, and / or HLA-DRB1, e.g., DRB1*0401. In some aspects, the MHC-presentable peptide sequences in Table 1B derived from or comprising any one of SEQ ID NO: 260 and SEQ ID NO: 278 are presentable on HLA-DRB1, e.g., HLA DRB1*0401. Table 2A. Exemplary MHC-presentable Peptide 19mers, 25mers, and 31mers.Table 2B. Exemplary MHC-presentable Peptides identified in at least 60% of donors

[0099] In some aspects, one or more of the MHC-presentable peptide sequences are generated from selected antigens, e.g., Chromogranin-A (CHGA), Carboxypeptidase A1 (CPA1), C1orf127 protein (C1orf127), Early growth response protein 4 (EGR4), Glutamate decarboxylase 2 (GAD2), Vitamin D-binding protein (GC), Guanine nucleotide-binding protein G(s) subunit alpha isoform XLas (GNAS), Glucose-6-phosphatase 2 (G6PC2 (IGRP)), Insulin (INS), Potassium channel subfamily K member 16 (KCNK16), Kinesin-like protein KIF1A (KIF1A), Neuroendocrine convertase 2 (PCSK2), Pancreas / duodenum homeobox protein 1 (PDX1), Proton-coupled zinc antiporter SLC30A8 (SLC30A8), or any combination thereof.

[0100] In some aspects, the MHC-presentable peptide for the present disclosure can be derived from Chromogranin-A (CHGA), which is also known as parathyroid secretory protein 1, CHGA, CGA, chromogranin A, Chromogranin A, PHES, or PHE5. Chromogranin A (CHGA) is found in secretory vesicles of neurons and endocrine cells. Specifically, CHGA is found in islet beta cell secretory granules in the pancreas and induces their generation. CHGA protein is a precursor to three biologically active peptides; vasostatin, pancreastatin, and parastatin. These peptides act as autocrine or paracrine negative modulators of the neuroendocrine system. Two other peptides, catestatin and chromofungin, have antimicrobial activity and antifungal activity, respectively.

[0101] Chromogranin A has been identified as autoantigen in type 1 diabetes and CHGA expression is elevated in patients with pheochromocytomas. A peptide fragment of ChgA located in the Vasostatin-1, namely ChgA29-42 has been identified as the antigenic MHC-presentable peptide recognized by diabetogenic BDC2.5 T cells from type 1 diabetes prone NOD mice. CHGA may also play a role in cancer progression, such as pancreatic cancer and prostate cancer. An exemplary accession number for Chromogranin A is P10645 (length: 457 aa). Additional accession numbers include B2R9E9, Q53FA8, Q6NR84, Q96E84, Q96GL7, Q9BQB5, and G3V2Q7.

[0102] The amino acid sequence for P10645 is shown below: P10645 (Length: 457) MRSAAVLALLLCAGQVTALPVNSPMNKGDTEVMKCIVEVISDTLSKPSPMPVSQECFETLRGDERILSILR HQNLLKELQDLALQGAKERAHQQKKHSGFEDELSEVLENQSSQAELKEAVEEPSSKDVMEKREDSKEAEKS GEATDGARPQALPEPMQESKAEGNNQAPGEEEEEEEEATNTHPPASLPSQKYPGPQAEGDSEGLSQGLVDR EKGLSAEPGWQAKREEEEEEEEEAEAGEEAVPEEEGPTVVLNPHPSLGYKEIRKGESRSEALAVDGAGKPG AEEAQDPEGKGEQEHSQQKEEEEEMAVVPQGLFRGGKSGELEQEEERLSKEWEDSKRWSKMDQLAKELTAE KRLEGQEEEEDNRDSSMKLSFRARAYGFRGPGPQLRRGWRPSSREDSLEAGLPLQVRGYPEEKKEEEGSAN RRPEDQELESLSAIEAELEKVAHQLQALRRG (SEQ ID NO.: 3)

[0103] Carboxypeptidase A1 (CPA1) is an enzyme that in humans is encoded by the CPA1 gene. Three different forms of human pancreatic procarboxypeptidase A have been isolated. The A1 and A2 forms are monomeric proteins with different biochemical properties. Carboxypeptidase A1 is a monomeric pancreatic exopeptidase. It is involved in zymogen inhibition. An exemplary accession number is P15085. Additional accession numbers include A4D1M1, Q53XU0, Q9BS67, Q9UCF2, C9JQ63, C9JUF9, C9JUZ4, and S4R433. A representative sequence (P15085) of the CPA1 is shown below: P15085 (Length: 419) MRGLLVLSVLLGAVFGKEDFVGHQVLRISVADEAQVQKVKELEDLEHLQLDFWRGPAHPGSPIDVRVPFPS IQAVKIFLESHGISYETMIEDVQSLLDEEQEQMFAFRSRARSTDTFNYATYHTLEEIYDFLDLLVAENPHL VSKIQIGNTYEGRPIYVLKFSTGGSKRPAIWIDTGIHSREWVTQASGVWFAKKITQDYGQDAAFTAILDTL DIFLEIVTNPDGFAFTHSTNRMWRKTRSHTAGSLCIGVDPNRNWDAGFGLSGASSNPCSETYHGKFANSEVEVKSIVDFVKDHGNIKAFISIHSYSQLLMYPYGYKTEPVPDQDELDQLSKAAVTALASLYGTKFNYGSIIK AIYQASGSTIDWTYSQGIKYSFTFELRDTGRYGFLLPASQIIPTAKETWLALLTIMEHTLNHPY (SEQ ID NO.: 248)

[0104] Chromosome 1 open reading frame 127 (C1orf127) is not well characterized and thus is a poorly understood protein encoded by chromosome 1 open reading frame 127. There are two known isoforms due to alternative splicing. C1orf127 is expressed in a variety of tissues, with the highest expression levels found in the stomach and pancreas. It is thought that the protein is excreted to the extracellular matrix and may be involved in development and adult homeostasis of the brain, skeletal muscle, testis, cardiac muscle, and the digestive system.

[0105] An exemplary accession number is G8JLG8. Additional accession numbers include A0AVG8, A6NKM7, Q5VXJ2, H0YBK5, H3BM07, K7EPZ7, B7ZLG7, B7ZLG9, and Q8N9H9 (and isoform Q8N9H9-2). The sequence of G8JLG8 (Length: 823) is shown below: MWGSPALAWAVWLACVQPTVFPWSLSFRSDTDKPSSAAEVLTEASSCWTDTVECFSDYMTLWIPRSHVEGL RRWLARTLHLPGTWRSPDHLDSSLAKCGYFLHLASDGDFLFRVQYSACFVQKEKANYRLEIRIFQKGVMGL ERSDRYIMKCPMLRSRLGQESVHCGPMFIQVSRPLPLWRDNRQTPWLLSLRGELVASLEDASLMGLYVDMN ATTVTVQSPRQGLLQRWEVLNTSAELLPLWLVSGHHAYSLEAACPPVSFQPESEVLVHIPKQRLGLVKRGS YIEETLSLRFLRVHQSNIFMVTENKDFVVVSIPAAGVLQVQRCQEVGGTPGTQAFYRVDLSLEFAEMAAPV LWTVESFFQCVGSGTESPASTAALRTTPSPPSPGPETPPAGVPPAASSQVWAAGPAAQEWLSRDLLHRPSD ALAKKGLGPFLQTAKPARRGQTSASILPRVVQAQRGPQPPPGEAGIPGHPTPPATLPSEPVEGVQASPWRP RPVLPTHPALTLPVSSDASSPSPPAPRPERPESLLVSGPSVTLTEGLGTVRPEQDPAKSPGSPLLLRGLSS GDVAAPEPIMGEPGQASEEFQPLARPWRATLAAEELVSHRSPGEPQETCSGTEVERPRQTGPGLPREGARG HMDLSSSEPSQDIEGPGLSILPARDATFSTPSVRQPDPSAWLSSGPELTGMPRVRLAAPLAVLPMEPLPPE PVRPAALLTPEASSVGGPDQARYLESAPGWPVGQEEWGVAHTSSPPSTQTLSLWAPTGVLLPSLVELEYPF QAGRGASLQQELTEPTLALSAESHRPPELQDSVEGLSERPSR (SEQ ID NO.: 2)

[0106] Early growth response protein 4 (EGR4) is also known as: EGR-4, NGFI-C, NGFIC, PAT133, early growth response 4, Early growth response protein 4, AT133. Early growth response protein 4 (EGR4) is a member of the early growth response family (EGF) of zinc finger transcription factors. EGR4 binds to DNA and is involved in the positive regulation of RNA polymerase II. Diseases associated with EGR4 include Schizophrenia 19 and Neuropathy, Congenital Hypomyelinating 1, Autosomal Recessive.

[0107] An exemplary accession number is Q05215. Additional accession numbers include B2RAE3, G3V1T5, Q2Z1P5, and A0A0C4DG96. The sequence of Q05215 (Length: 589) is: MAVARGVGSPEPAPPQLYKWGGCGLGEPGSALERRGAAARGRCGRARAPRLPDSFPRGECPKPGARAPRSV RCGEPLPPASPPPARPQAQRARPRAPHSRRRAMLHLSEFSEPDALLVKSTEGCCAEPSAELPRLPARDAPA ATGYPGAGDFLSWALNSCGASGDLADSCFLEGPAPTPPPGLSYSGSFFIQAVPEHPHDPEALFNLMSGILG LAPFPGPEAAASRSPLDAPFPAGSDALLPGPPDLYSPDLGAAPFPEAFWEASPCAGAPSQCLYEPQLSPPD VKPGLRAPPASPALDAVSAFKGPYAPWELLSVGAPGNCGSQGDYQAAPEARFPVIGTKIEDLLSISCPAEL PAVPANRLYPSGAYDAFPLAPGDLGEGAEGLPGLLTPPSGEGGSSGDGGEFLASTQPQLSPLGLRSAAAAD FPKPLVADIPGSSGVAAPPVPPPPPTPFPQAKARRKGRRGGKCSTRCFCPRPHAKAFACPVESCVRSFARS DELNRHLRIHTGHKPFQCRICLRNFSRSDHLTTHVRTHTGEKPFACDVCGRRFARSDEKKRHSKVHLKQKA RAEERLKGLGFYSLGLSFASL (SEQ ID NO.: 287)

[0108] Glutamate decarboxylase 2 (GAD2) is also known as: GAD2, GAD65, glutamate decarboxylase 2. Glutamate decarboxylase 2 is an enzyme that in humans is encoded by the GAD2 gene. This gene encodes one of several forms of glutamic acid decarboxylase which catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA). GAD2 encodes the islet specific glutamic acid decarboxylase (GAD65) and has been identified as an autoantibody eliciting an autoreactive T cell response in insulin-dependent diabetes.

[0109] An exemplary accession number for GAD2 is Q05329. Additional accession numbers include Q9UD87, A0A3B3IU09, and Q5VZ31. The sequence of Q05329 (Length: 585) is shown below: MASPGSGFWSFGSEDGSGDSENPGTARAWCQVAQKFTGGIGNKLCALLYGDAEKPAESGGSQPPRAAARKA ACACDQKPCSCSKVDVNYAFLHATDLLPACDGERPTLAFLQDVMNILLQYVVKSFDRSTKVIDFHYPNELL QEYNWELADQPQNLEEILMHCQTTLKYAIKTGHPRYFNQLSTGLDMVGLAADWLTSTANTNMFTYEIAPVF VLLEYVTLKKMREIIGWPGGSGDGIFSPGGAISNMYAMMIARFKMFPEVKEKGMAALPRLIAFTSEHSHFS LKKGAAALGIGTDSVILIKCDERGKMIPSDLERRILEAKQKGFVPFLVSATAGTTVYGAFDPLLAVADICK KYKIWMHVDAAWGGGLLMSRKHKWKLSGVERANSVTWNPHKMMGVPLQCSALLVREEGLMQNCNQMHASYL FQQDKHYDLSYDTGDKALQCGRHVDVFKLWLMWRAKGTTGFEAHVDKCLELAEYLYNIIKNREGYEMVFDG KPQHTNVCFWYIPPSLRTLEDNEERMSRLSKVAPVIKARMMEYGTTMVSYQPLGDKVNFFRMVISNPAATH QDIDFLIEEIERLGQDL (SEQ ID NO.: 289)

[0110] Vitamin D-binding protein (GC) is also known as: DBP, VDB, Gc protein-derived macrophage activating factor, Gc-MAF; GcMAF, Gc-globulin, Group-specific component, Gc, Vitamin D-binding protein-macrophage activating factor (DBP-maf). Vitamin D-binding protein belongs to the albumin gene family, together with human serum albumin and alpha-fetoprotein. It is a multifunctional protein found in plasma, ascitic fluid, cerebrospinal fluid and on the surface of many cell types. It is able to bind the various forms of vitamin D including ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3), the 25-hydroxylated forms (calcifediol), and the active hormonal product, 1,25-dihydroxyvitamin D (calcitriol). The major proportion of vitamin D in blood is bound to this protein. It transports vitamin D metabolites between skin, liver and kidney, and then on to the various target tissues. As Gc protein-derived macrophage activating factor it is a Macrophage Activating Factor (MAF) that has been tested for use as a cancer treatment that would activate macrophages against cancer cells.

[0111] An exemplary accession number is P02774. Additional accession numbers include B4DPP2, D6RAK8, Q16309, Q16310, Q53F31, Q6GTG1, D6RBJ7, D6RF20, and D6RF35. The sequence of P02774 is shown below: P02774 (Length: 474) MKRVLVLLLAVAFGHALERGRDYEKNKVCKEFSHLGKEDFTSLSLVLYSRKFPSGTFEQVSQLVKEVVSLT EACCAEGADPDCYDTRTSALSAKSCESNSPFPVHPGTAECCTKEGLERKLCMAALKHQPQEFPTYVEPTNDEICEAFRKDPKEYANQFMWEYSTNYGQAPLSLLVSYTKSYLSMVGSCCTSASPTVCFLKERLQLKHLSLLT TLSNRVCSQYAAYGEKKSRLSNLIKLAQKVPTADLEDVLPLAEDITNILSKCCESASEDCMAKELPEHTVK LCDNLSTKNSKFEDCCQEKTAMDVFVCTYFMPAAQLPELPDVELPTNKDVCDPGNTKVMDKYTFELSRRTH LPEVFLSKVLEPTLKSLGECCDVEDSTTCFNAKGPLLKKELSSFIDKGQELCADYSENTFTEYKKKLAERL KAKLPDATPTELAKLVNKHSDFASNCCSINSPPLYCDSEIDAELKNIL (SEQ ID NO.: 290)

[0112] Guanine nucleotide-binding protein G(s) subunit alpha isoform XLas (GNAS) is also known as: AHO; GSA; GSP; POH; GPSA; NESP; NESP55; SCG6; SgVI; GNAS1; PITA3; C20orf45. Guanine Nucleotide binding protein, Alpha Stimulating activity polypeptide (GNAS) is encoded by the GNAS complex gene locus in humans, which has a highly complex imprinted expression pattern resulting in several transcript isoforms and alternative gene products. GNAS is a key component of G protein-coupled receptor-regulated adenylyl cyclase signal transduction pathways. Traditional G protein-coupled receptor signaling proceeds primarily through Gsα-long and Gsα-short, the most abundant, ubiquitously-expressed protein products of this gene. As a result, mutations in GNAS are associated with several diseases and disorders including Albright hereditary osteodystrophy, psuedohypoparathyroidism type Ia and Ib, pseudopseudohypoparathyroidism, McCune-Albright syndrome, Myxoma, progressive osseous heteroplasia, polyostotic fibrous dysplasia of bone, and some pituitary tumors. An exemplary accession number is Q5JWF2 and the isoform sequences Q5JWF2-2 and Q5JWF2-3. Additional accession numbers include A2A2S3, E1P5G3, O75684, O75685, Q5JW67, A0A0A0MR13, A0A590UJ46, A0A590UJ47, A0A590UJC9, A0A590UJF0, A0A590UJQ9, A0A590UJS2, A0A590UJX3, A0A590UJX6, A0A590UJY2, A0A590UK00, A0A590UK28, A0A7I2V5R6, A0A804HIH4, A0A8I5F5B5, A2A2R6, A2A2S1, B0AZR9, O95467, P84996, P63092, P63092-2, P63092-3, and P63092-4.

[0113] The sequence of Q5JWF2 (Length: 1037) is shown below: MGVRNCLYGNNMSGQRDIPPEIGEQPEQPPLEAPGAAAPGAGPSPAEEMETEPPHNEPIPVENDGEACGPP EVSRPNFQVLNPAFREAGAHGSYSPPPEEAMPFEAEQPSLGGFWPTLEQPGFPSGVHAGLEAFGPALMEPG AFSGARPGLGGYSPPPEEAMPFEFDQPAQRGCSQLLLQVPDLAPGGPGAAGVPGAPPEEPQALRPAKAGSR GGYSPPPEETMPFELDGEGFGDDSPPPGLSRVIAQVDGSSQFAAVAASSAVRLTPAANAPPLWVPGAIGSP SQEAVRPPSNFTGSSPWMEISGPPFEIGSAPAGVDDTPVNMDSPPIALDGPPIKVSGAPDKRERAERPPVE EEAAEMEGAADAAEGGKVPSPGYGSPAAGAASADTAARAAPAAPADPDSGATPEDPDSGTAPADPDSGAFA ADPDSGAAPAAPADPDSGAAPDAPADPDSGAAPDAPADPDAGAAPEAPAAPAAAETRAAHVAPAAPDAGAP TAPAASATRAAQVRRAASAAPASGARRKIHLRPPSPEIQAADPPTPRPTRASAWRGKSESSRGRRVYYDEG VASSDDDSSGDESDDGTSGCLRWFQHRRNRRRRKPQRNLLRNFLVQAFGGCFGRSESPQPKASRSLKVKKV PLAEKRRQMRKEALEKRAQKRAEKKRSKLIDKQLQDEKMGYMCTHRLLLLGAGESGKSTIVKQMRILHVNG FNGEGGEEDPQAARSNSDGEKATKVQDIKNNLKEAIETIVAAMSNLVPPVELANPENQFRVDYILSVMNVP DFDFPPEFYEHAKALWEDEGVRACYERSNEYQLIDCAQYFLDKIDVIKQADYVPSDQDLLRCRVLTSGIFE TKFQVDKVNFHMFDVGGQRDERRKWIQCFNDVTAIIFVVASSSYNMVIREDNQTNRLQEALNLFKSIWNNR WLRTISVILFLNKQDLLAEKVLAGKSKIEDYFPEFARYTTPEDATPEPGEDPRVTRAKYFIRDEFLRISTA SGDGRHYCYPHFTCAVDTENIRRVFNDCRDIIQRMHLRQYELL (SEQ ID NO.: 1)

[0114] Glucose-6-phosphatase 2 (G6PC2) is also known as G-6-Pase 2, G6Pase 2, or Islet- specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and is an enzyme belonging to the glucose-6-phosphatase catalytic subunit family. These enzymes are part of a multicomponent integral membrane system that catalyzes the hydrolysis of glucose-6-phosphate, the terminal step in gluconeogenic and glycogenolytic pathways, allowing the release of glucose into the bloodstream. The family member encoded by this gene is found in pancreatic islets and does not exhibit phosphohydrolase activity, but it is a major target of cell-mediated autoimmunity in diabetes. Several alternatively spliced transcript variants of this gene have been described, but their biological validity has not been determined.

[0115] An exemplary accession number of G6PC2 is Q9NQR9 and isoforms Q9NQR9-2 and Q9NQR9-3. Additional accession numbers include E9PAX2, Q6AHZ0, and C9IYU7. The sequence of Q9NQR9 (Length: 355) is shown below: MDFLHRNGVLIIQHLQKDYRAYYTFLNFMSNVGDPRNIFFIYFPLCFQFNQTVGTKMIWVAVIGDWLNLIF KWILFGHRPYWWVQETQIYPNHSSPCLEQFPTTCETGPGSPSGHAMGASCVWYVMVTAALSHTVCGMDKFS ITLHRLTWSFLWSVFWLIQISVCISRVFIATHFPHQVILGVIGGMLVAEAFEHTPGIQTASLGTYLKTNLF LFLFAVGFYLLLRVLNIDLLWSVPIAKKWCANPDWIHIDTTPFAGLVRNLGVLFGLGFAINSEMFLLSCRG GNNYTLSFRLLCALTSLTILQLYHFLQIPTHEEHLFYVLSFCKSASIPLTVVAFIPYSVHMLMKQSGKKSQ (SEQ ID NO.: 288)

[0116] Insulin (INS), also known as IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10, and PNDM4 is a peptide hormone produced by islet beta cells. Insulin regulates metabolism by promoting absorption of glucose from the blood into liver, fat, and skeletal muscle cells.

[0117] An exemplary accession number is I3WAC9. Additional accession numbers include P01308, F8WCM5, and Q5EEX2. The sequence of I3WAC9 (Length: 110) is shown below: MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGG PGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN (SEQ ID NO.: 291)

[0118] Potassium channel subfamily K member 16 (KCNK16) is also known as: KCNK16, K2p16.1, TALK-1, TALK1, potassium two pore domain channel subfamily K member 16. Potassium channel subfamily K member 16 (K2P16.1) is encoded by the KCNK16 gene. K2P16.1 is a member of the family of potassium channel proteins containing two pore-forming P domains and is predominantly expressed in the pancreas. An exemplary accession number is Q96T55, and the secondary accession numbers include: B5TJL9, Q2M2N9, Q5TCF3, Q6X6Z3, Q6X6Z4, Q6X6Z5, D6RC57, and Q9H591.

[0119] Several isoforms of KCNK16 are known. One isoform has Accession no. Q96T55 (Length: 309) with the following sequence:MPSAGLCSCWGGRVLPLLLAYVCYLLLGATIFQLLERQAEAQSRDQFQLEKLRFLENYTCLDQWAMEQFVQ VIMEAWVKGVNPKGNSTNPSNWDFGSSFFFAGTVVTTIGYGNLAPSTEAGQVFCVFYALLGIPLNVIFLNH LGTGLRAHLAAIERWEDRPRRSQVLQVLGLALFLTLGTLVILIFPPMVFSHVEGWSFSEGFYFAFITLSTI GFGDYVVGTDPSKHYISVYRSLAAIWILLGLAWLALILPLGPLLLHRCCQLWLLSLRQGCGAKAAPGRRPR RGSTAARGVQVTPQDFPISKKGLGS (SEQ ID NO.: 4)

[0120] Kinesin-like protein KIF1A (KIF1A) is also known as: KIF1A, ATSV, C2orf20, HSN2C, MRD9, SPG30, UNC104, kinesin family member 1A. Kinesin-like protein (KIF1A) is a microtubule motorprotein involved in the transport of vesicles and organelles. KIF1A is highly expressed in neurons and is essential for neuronal survival, but is also lowly expressed in the heart, testes, pancrease, adrenal glands, and pituitary glands. KIF1A-mediated anterograde axonal transport is of critical importance for the development and maintenance of the nervous system. Mutations in KIF1A have been identified as associated with Hereditary Spastic Paraplegia (HSP), Nonsyndromic Intellectual Disability (NID), and Hereditary Sensory and Autonomic Neuropathy type II (HSAN II). An exemplary accession number is Q12756. Additional accession numbers include: B0I1S5, F5H045, O95068, Q13355, Q14752, Q2NKJ6, Q4LE42, Q53T78, Q59GH1, Q63Z40, Q6P1R9, Q7KZ57, A0A3B3IT28, A0A3B3ITE5, A0A3B3ITF7, A0A3B3ITK3, A0A3B3ITW4, A0A3B3ITW6, A0A3B3IU40, A0A3B3IUA1, A0A3F2YNW9, A0A6Q8PFJ8, A0A6Q8PFL2, A0A6Q8PFR1, A0A6Q8PFR5, A0A6Q8PGE4, A0A6Q8PGW8, A0A6Q8PH56, A0A6Q8PHQ5, C9JBH1, H7C0K6, H7C3Y8 and A0A6Q8PFE9. Some isoform sequences are shown below: Q12756-3 (Length: 1,791) MAGASVKVAVRVRPFNSREMSRDSKCIIQMSGSTTTIVNPKQPKETPKSFSFDYSYWSHTSPEDINYASQK QVYRDIGEEMLQHAFEGYNVCIFAYGQTGAGKSYTMMGKQEKDQQGIIPQLCEDLFSRINDTTNDNMSYSV EVSYMEIYCERVRDLLNPKNKGNLRVREHPLLGPYVEDLSKLAVTSYNDIQDLMDSGNKARTVAATNMNET SSRSHAVFNIIFTQKRHDAETNITTEKVSKISLVDLAGSERADSTGAKGTRLKEGANINKSLTTLGKVISA LAEMDSGPNKNKKKKKTDFIPYRDSVLTWLLRENLGGNSRTAMVAALSPADINYDETLSTLRYADRAKQIR CNAVINEDPNNKLIRELKDEVTRLRDLLYAQGLGDITDTNTVPGGPKLTNALVGMSPSSSLSALSSRAASV SSLHERILFAPGSEEAIERLKETEKIIAELNETWEEKLRRTEAIRMEREALLAEMGVAMREDGGTLGVFSP KKTPHLVNLNEDPLMSECLLYYIKDGITRVGREDGERRQDIVLSGHFIKEEHCVFRSDSRGGSEAVVTLEP CEGADTYVNGKKVTEPSILRSGNRIIMGKSHVFRFNHPEQARQERERTPCAETPAEPVDWAFAQRELLEKQ GIDMKQEMEQRLQELEDQYRREREEATYLLEQQRLDYESKLEALQKQMDSRYYPEVNEEEEEPEDEVQWTE RECELALWAFRKWKWYQFTSLRDLLWGNAIFLKEANAISVELKKKVQFQFVLLTDTLYSPLPPDLLPPEAA KDRETRPFPRTIVAVEVQDQKNGATHYWTLEKLRQRLDLMREMYDRAAEVPSSVIEDCDNVVTGGDPFYDR FPWFRLVGSSAISGCNSYPLLNTCMSERMAALTPSPTFSSPDSDATEPAEEQSVGEEEEEEEEEEDEEEED LEDDVFPEHALCDGRDPFYDRPPLFSLVGRAFVYLSNLLYPVPLVHRVAIVSEKGEVKGFLRVAVQAISAD EEAPDYGSGVRQSGTAKISFDDQHFEKFQSESCPVVGMSRSGTSQEELRIVEGQGQGADVGPSADEVNNNT CSAVPPEGLLLDSSEKAALDGPLDAALDHLRLGNTFTFRVTVLQASSISAEYADIFCQFNFIHRHDEAFST EPLKNTGRGPPLGFYHVQNIAVEVTKSFIEYIKSQPIVFEVFGHYQQHPFPPLCKDVLSPLRPSRRHFPRV MPLSKPVPATKLSTLTRPCPGPCHCKYDLLVYFEICELEANGDYIPAVVDHRGGMPCMGTFLLHQGIQRRI TVTLLHETGSHIRWKEVRELVVGRIRNTPETDESLIDPNILSLNILSSGYIHPAQDDRTFYQFEAAWDSSM HNSLLLNRVTPYREKIYMTLSAYIEMENCTQPAVVTKDFCMVFYSRDAKLPASRSIRNLFGSGSLRASESN RVTGVYELSLCHVADAGSPGMQRRRRRVLDTSVAYVRGEENLAGWRPRSDSLILDHQWELEKLSLLQEVEKTRHYLLLREKLETAQRPVPEALSPAFSEDSESHGSSSASSPLSAEGRPSPLEAPNERQRELAVKCLRLLTH TFNREYTHSHVCVSASESKLSEMSVTLLRDPSMSPLGVATLTPSSTCPSLVEGRYGATDLRTPQPCSRPAS PEPELLPEADSKKLPSPARATETDKEPQRLLVPDIQEIRVSPIVSKKGYLHFLEPHTSGWARRFVVVRRPY AYMYNSDKDTVERFVLNLATAQVEYSEDQQAMLKTPNTFAVCTEHRGILLQAASDKDMHDWLYAFNPLLAG TIRSKLSRRRSAQMRV (SEQ ID NO.: 292)

[0121] Neuroendocrine convertase 2 (PCSK2) is also known as: PCSK2, NEC 2, NEC-2, NEC2, PC2, SPC2, proprotein convertase subtilisin / kexin type 2, neuroendocrine convertase 2, prohormone convertase 2. Protein convertase 2 (PCSK2) is a serine protease and proprotein convertase responsible for the first step in the maturation of many neuroendocrine peptides. For example, PCSK2 is involved in the conversion of proinsulin to insulin intermediates, and in glucagon biosynthesis. Diseases associated with PCSK2 include Mahvash Disease and Insulinoma. Additionally, genetic polymorphisms in PCSK2 have been identified as risk alleles for Type 2 Diabetes.

[0122] An exemplary accession number is P16519 and isoforms P16519-2 and P16519-3. Additional accession numbers include: B1ANH9, B4DFQ3, Q14927, Q5JYQ1, Q8IWA8, Q9NQG3, Q9NUG1, or Q9UJC6. The sequences for P16519 and isoforms P16519-2 and P16519- 3 areshown below: P16519 (Length: 638) MKGGCVSQWKAAAGFLFCVMVFASAERPVFTNHFLVELHKGGEDKARQVAAEHGFGVRKLPFAEGLYHFYH NGLAKAKRRRSLHHKQQLERDPRVKMALQQEGFDRKKRGYRDINEIDINMNDPLFTKQWYLINTGQADGTP GLDLNVAEAWELGYTGKGVTIGIMDDGIDYLHPDLASNYNAEASYDFSSNDPYPYPRYTDDWFNSHGTRCA GEVSAAANNNICGVGVAYNSKVAGIRMLDQPFMTDIIEASSISHMPQLIDIYSASWGPTDNGKTVDGPREL TLQAMADGVNKGRGGKGSIYVWASGDGGSYDDCNCDGYASSMWTISINSAINDGRTALYDESCSSTLASTF SNGRKRNPEAGVATTDLYGNCTLRHSGTSAAAPEAAGVFALALEANLGLTWRDMQHLTVLTSKRNQLHDEV HQWRRNGVGLEFNHLFGYGVLDAGAMVKMAKDWKTVPERFHCVGGSVQDPEKIPSTGKLVLTLTTDACEGK ENFVRYLEHVQAVITVNATRRGDLNINMTSPMGTKSILLSRRPRDDDSKVGFDKWPFMTTHTWGEDARGTW TLELGFVGSAPQKGVLKEWTLMLHGTQSAPYIDQVVRDYQSKLAMSKKEELEEELDEAVERSLKSILNKN (SEQ ID NO.: 293)

[0123] Pancreas / duodenum homeobox protein 1 (PDX1), also known as Glucose-sensitive factor (GSF), Insulin promoter factor 1 (IPF-1), Insulin upstream factor 1 (IUF-1), Islet / duodenum homeobox-1 (IDX-1), and Somatostatin-transactivating factor 1 (STF-1), is a transcription factor in the ParaHox gene cluster. In vertebrates, Pdx1 is necessary for pancreatic development, including β-cell maturation, and duodenal differentiation. In pancreatic development, Pdx1 is expressed by a population of cells in the posterior foregut region of the definitive endoderm, and Pdx1+ epithelial cells give rise to the developing pancreatic buds, and eventually, the whole of the pancreas—its exocrine, endocrine, and ductal cell populations. Pancreatic Pdx1+ cells first arise at mouse embryonic day 8.5-9.0 (E8.5-9.0), and Pdx1 expression continues until E12.0-E12.5.

[0124] Experiments in animal models have shown that a reduction in Pdx1 expression can cause symptoms that are characteristic of Diabetes mellitus type 1 and Diabetes mellitus type 2. Furthermore, expression of Pdx1 is lost in gastric cancers, suggesting a role for the gene as a tumor suppressor. Maturity onset diabetes of the young (Type 4) can be caused by heterozygous mutations in Pdx1. The fat sand rat Psammomys obesus, a species with susceptibility to Diabetes mellitus type 2 symptoms, has a highly divergent Pdx1 gene sequence compared with other mammals. An exemplary accession number is P52945, and the secondary accession numbers are O60594 and Q5VYW2. The sequence for P52945 (Length: 283) is shown below: MNGEEQYYAATQLYKDPCAFQRGPAPEFSASPPACLYMGRQPPPPPPHPFPGALGALEQGSPPDISPYEVP PLADDPAVAHLHHHLPAQLALPHPPAGPFPEGAEPGVLEEPNRVQLPFPWMKSTKAHAWKGQWAGGAYAAE PEENKRTRTAYTRAQLLELEKEFLFNKYISRPRRVELAVMLNLTERHIKIWFQNRRMKWKKEEDKKRGGGT AVGGGGVAEPEQDCAVTSGEELLALPPPPPPGGAVPPAAPVAAREGRLPPGLSASPQPSSVAPRRPQEPR (SEQ ID NO.: 294)

[0125] Proton-coupled zinc antiporter SLC30A8 (SLC30A8) is also known as: SLC30A8, ZNT8, ZnT-8, solute carrier family 30 member 8. Soluble carrier family 30 member 8 (SLC30A8) is a zinc transporter involved in insulin secretion. SLC30A8 is critical for the accumulation of zinc into beta cell secretory granules and the maintenance of insulin stored as tightly packaged hexamers. Twelve variants of the SLC30A8 gene have been identified as associated with increased risk of developing Type 2 diabetes. However, loss-of-function mutations appear to greatly reduce the risk of diabetes. An exemplary accession number for SLC30A8 is Q8IWU4 and isoform Q8IWU4-2. Additional accession numbers include A0AVP9, A5YM39, B4DPE0, Q8TCL3, A0A096LNR0, A0A096LPF3, and E5RG87. The sequence for Q8IWU4 (Length: 369) is shown below: MEFLERTYLVNDKAAKMYAFTLESVELQQKPVNKDQCPRERPEELESGGMYHCHSGSKPTEKGANEYAYAK WKLCSASAICFIFMIAEVVGGHIAGSLAVVTDAAHLLIDLTSFLLSLFSLWLSSKPPSKRLTFGWHRAEIL GALLSILCIWVVTGVLVYLACERLLYPDYQIQATVMIIVSSCAVAANIVLTVVLHQRCLGHNHKEVQANAS VRAAFVHALGDLFQSISVLISALIIYFKPEYKIADPICTFIFSILVLASTITILKDFSILLMEGVPKSLNY SGVKELILAVDGVLSVHSLHIWSLTMNQVILSAHVATAASRDSQVVRREIAKALSKSFTMHSLTIQMESPV DQDPDCLFCEDPCD (SEQ ID NO.: 5)

[0126] In some aspects, the MHC-presentable peptides identified by a combination of various assays herein have improved immunogenicity, tolerogenic property, or any combination thereof and are suitable to be used for tolerogenic vaccines. Compositions

[0127] The present disclosure provides a composition comprising a nucleotide sequence (e.g., mRNA) that encodes an amino acid sequence comprising one or more MHC-presentable peptide sequences disclosed herein, or the amino acid sequence comprising one or more MHC-presentablepeptides, wherein at least one of the MHC-presentable peptides is capable of inducing a tolerizing immune response against Type I diabetes in a subject in need thereof. The present disclosure also provides a composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

[0128] In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of one or more MHC- presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B). In some aspects, the composition of the present disclosure comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B) except MHC-presentable peptides comprising, consisting essentially of, or consisting of FTYEIAPVFVLLEYV (SEQ ID NO: 94), LYHFLQIPTHEEHLF (SEQ ID NO: 174), IDFHYPNELLQEYNW (SEQ ID NO: 54), DQELESLSAIEAELE (SEQ ID NO: 50), ISNPAATHQDIDFLI (SEQ ID NO: 58), ENPGTARAWCQVAQK (SEQ ID NO: 140), HLVEALYLVCGERGF (SEQ ID NO: 128), LKDFSILLMEGVPKS (SEQ ID NO: 201), GTTVYGAFDPLLAVA (SEQ ID NO: 176), AATHQDIDFLIEEIE (SEQ ID NO: 206), and RAKYFIRDEFLRIST (SEQ ID NO: 211), or (ii) the amino acid sequence comprising an MHC- presentable peptide which comprises at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B) except MHC-presentable peptidescomprising, consisting essentially of, or consisting of FTYEIAPVFVLLEYV (SEQ ID NO: 94), LYHFLQIPTHEEHLF (SEQ ID NO: 174), IDFHYPNELLQEYNW (SEQ ID NO: 54), DQELESLSAIEAELE (SEQ ID NO: 50), ISNPAATHQDIDFLI (SEQ ID NO: 58), ENPGTARAWCQVAQK (SEQ ID NO: 140), HLVEALYLVCGERGF (SEQ ID NO: 128), LKDFSILLMEGVPKS (SEQ ID NO: 201), GTTVYGAFDPLLAVA (SEQ ID NO: 176), AATHQDIDFLIEEIE (SEQ ID NO: 206), and RAKYFIRDEFLRIST (SEQ ID NO: 211).

[0129] In some aspects, the composition of the present disclosure comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B) except MHC-presentable peptides comprising, consisting essentially of, or consisting of any one of SEQ ID NOs: 10, 18, 22, 30, 50, 54, 58, 62, 82, 83, 84, 91, 94, 109, 110, 113, 118, 119, 122, 128, 137, 140, 141, 144, 146, 153, 157, 172, 174, 176, 179, 181, 182, 186, 187, 194, 196, 201, 204, 206, 207, 209, 210, 211, 221, 222, 223, 224, 244, 246, 247, 258, and 259, or (ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of one or more MHC-presentable peptide sequences set forth in Table 1A (or for example, Table 2A (15mer) or Table 2B) except MHC-presentable peptides comprising, consisting essentially of, or consisting of FTYEIAPVFVLLEYV (SEQ ID NO: 94), LYHFLQIPTHEEHLF (SEQ ID NO: 174), IDFHYPNELLQEYNW (SEQ ID NO: 54), DQELESLSAIEAELE (SEQ ID NO: 50), ISNPAATHQDIDFLI (SEQ ID NO: 58), ENPGTARAWCQVAQK (SEQ ID NO: 140), HLVEALYLVCGERGF (SEQ ID NO: 128), LKDFSILLMEGVPKS (SEQ ID NO: 201), GTTVYGAFDPLLAVA (SEQ ID NO: 176), AATHQDIDFLIEEIE (SEQ ID NO: 206), and RAKYFIRDEFLRIST (SEQ ID NO: 211).

[0130] In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or (ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 8 amino acids, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 amino acids of one or more MHC-presentable peptide sequence set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B). For example, with respect to MHC-presentable peptide LWVVPGAIGSPSQEA (SEQ ID NO: 6) (15mer), the nucleotidesequence of the present disclosure encodes an amino acid sequence comprising an MHC- presentable peptide selected from LWVVPGAIGSPSQEA (SEQ ID NO: 6) (15mer), LWVPGAIGSPSQEA (SEQ ID NO: 249)(14mer missing one C terminal amino acid from SEQ ID NO: 6), WVPGAIGSPSQEAV (SEQ ID NO: 250) (14mer missing one N terminal amino acid from SEQ ID NO: 6), LWVPGAIGSPSQE (SEQ ID NO: 251) (13mer missing two C terminal amino acid from SEQ ID NO: 6), VPGAIGSPSQEAV (SEQ ID NO: 252) (13mer missing two N terminal amino acid from SEQ ID NO: 6), WVPGAIGSPSQEA (SEQ ID NO: 253) (13mer missing one N terminal amino acid and one C terminal amino acid from SEQ ID NO: 6), LWVPGAIGSPSQ (SEQ ID NO: 254) (12mer missing three C terminal amino acids from SEQ ID NO: 6), WVPGAIGSPSQE (SEQ ID NO: 255) (12mer missing one N terminal amino acid and two C terminal amino acids from SEQ ID NO: 6), VPGAIGSPSQEA (SEQ ID NO: 256) (12mer missing two N terminal amino acids and one C terminal amino acid from SEQ ID NO: 6), VPGAIGSPSQEA (SEQ ID NO: 257) (12mer missing three N terminal amino acids from SEQ ID NO: 6), LWVVPGAIGSP (SEQ ID NO: 296) (11mer missing four C terminal amino acids from SEQ ID NO: 6), WVVPGAIGSPS (SEQ ID NO: 297) (11mer missing one N terminal amino acids and three C terminal amino acids from SEQ ID NO: 6), VVPGAIGSPSQ (SEQ ID NO: 298) (11mer missing two N terminal amino acids and two C terminal amino acids from SEQ ID NO: 6), VPGAIGSPSQE (SEQ ID NO: 299) (11mer missing three N terminal amino acids and one C terminal amino acid from SEQ ID NO: 6), PGAIGSPSQEA (SEQ ID NO: 300) (11mer missing four N terminal amino acids from SEQ ID NO: 6), LWVVPGAIGS (SEQ ID NO: 301) (10mer missing five C terminal amino acids from SEQ ID NO: 6), WVVPGAIGSP (SEQ ID NO: 302) (10mer missing one N terminal amino acids and four C terminal amino acids from SEQ ID NO: 6), VVPGAIGSPS (SEQ ID NO: 303) (10mer missing two N terminal amino acids and three C terminal amino acids from SEQ ID NO: 6), VPGAIGSPSQ (SEQ ID NO: 304) (10mer missing three N terminal amino acids and two C terminal amino acids from SEQ ID NO: 6), PGAIGSPSQE (SEQ ID NO: 305) (10mer missing four N terminal amino acids and one C terminal amino acids from SEQ ID NO: 6), GAIGSPSQEA (SEQ ID NO: 306) (10mer missing five N terminal amino acids from SEQ ID NO: 6), LWVVPGAIG (SEQ ID NO: 307) (9mer missing six C terminal amino acids from SEQ ID NO: 6), WVVPGAIGS(SEQ ID NO: 308) (9mer missing one N terminal amino acid and five C terminal amino acids from SEQ ID NO: 6), VVPGAIGSP (SEQ ID NO: 309) (9mer missing two N terminal amino acids and four C terminal amino acids from SEQ ID NO: 6), VPGAIGSPS (SEQ ID NO: 310) (9mer missing three N terminal amino acids and three C terminal amino acids from SEQ ID NO: 6),VPGAIGSPSQ (SEQ ID NO: 311) (9mer missing four Nterminal amino acids and two C terminal amino acids from SEQ ID NO: 6), GAIGSPSQE (SEQ ID NO: 312) (9mer missing five N terminal amino acids and one C terminal amino acids from SEQ ID NO: 6), AIGSPSQEA (SEQ ID NO: 313) (9mer missing six N terminal amino acids from SEQ ID NO: 6), LWVVPGAI (SEQ ID NO: 314) (8mer missing seven C terminal amino acids from SEQ ID NO: 6), WVVPGAIG (SEQ ID NO: 315) (8mer missing one N terminal amino acid and six C terminal amino acids from SEQ ID NO: 6), VVPGAIGS (SEQ ID NO: 316) (8mer missing two N terminal amino acids and five C terminal amino acids from SEQ ID NO: 6), VPGAIGSP (SEQ ID NO: 317) (8mer missing three N terminal amino acids and four C terminal amino acids from SEQ ID NO: 6), PGAIGSPS (SEQ ID NO: 318) (8mer missing four N terminal amino acids and three C terminal amino acids from SEQ ID NO: 6), GAIGSPSQ (SEQ ID NO: 319) (8mer missing five N terminal amino acids and two C terminal amino acids from SEQ ID NO: 6), AIGSPSQE (SEQ ID NO: 320) (8mer missing six N terminal amino acids and one C terminal amino acids from SEQ ID NO: 6), and IGSPSQEA (SEQ ID NO: 321) (8mer missing seven N terminal amino acids from SEQ ID NO: 6). For any other MHC-presentable peptides disclosed in Table 1A, Table 1B, Table 2A, and / or Table 2B, the amino acid sequence encoded by the nucleotide sequence of the present disclosure comprises, consists essentially of, or consists of an MHC-presentable peptide which is any contiguous amino acids of at least eight, at least nine, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 15 amino acids of the MHC- presentable peptides in Table 1A, Table 1B, Table 2A, and / or Table 2B as exemplified above.

[0131] In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 35 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or (ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 35 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mers) or Table 2B). In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 19 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or(ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 19 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B). In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 19 amino acids of one or more MHC-presentable peptide sequences set forth in Table 2A (e.g., SEQ ID NO: 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, or 75) and Table 2B, or (ii) the amino acid sequence comprising an MHC- presentable peptide which comprises at least 19 amino acids of one or more MHC-presentable peptide sequences set forth in Table 2A (e.g., SEQ ID NO: 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, or 75) Table 2B. In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 25 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or (ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 25 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B). In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 25 amino acids of one or more MHC-presentable peptide sequences set forth in Table 2A (e.g., SEQ ID NO: 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, or 76) or Table 2B, or (ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 25 amino acids of one or more MHC-presentable peptide sequences set forth in Table 2A (e.g., SEQ ID NO: 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, or 76) or Table 2B. In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 31 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), or (ii) the amino acid sequence comprising an MHC- presentable peptide which comprises at least 31 amino acids of one or more MHC-presentable peptide sequences set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B). In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises at least 31 amino acids of one or more MHC-presentable peptide sequences set forth in Table 2A (e.g., SEQ ID NO: 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, or 77) or Table 2B, or (ii) the amino acid sequence comprising an MHC-presentable peptide which comprises at least 31 amino acids of oneor more MHC-presentable peptide sequences set forth in Table 2 (e.g., SEQ ID NO: 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, or 77) or Table 2B.

[0132] In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising one or more MHC-presentable peptide sequences set forth in Table 3, or (ii) the amino acid sequence comprising one or more MHC-presentable peptide sequences set forth in Table 3. In some aspects, additional MHC-presentable peptides similar to Table 3 can be generated for any one or more MHC-presentable peptide sequences in Table 1A. Table 3. Exemplary Peptides (SEQ ID NO: 6) that can have N terminal and / or C terminal spacers

[0133] In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises the MHC- presentable peptide sequence as set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), e.g., SEQ ID NO: 6, or (ii) the amino acid sequence comprising the MHC- presentable peptide sequence as set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), e.g., SEQ ID NO: 6, wherein the MHC-presentable peptide further comprises a N terminal spacer comprising one amino acid (e.g., P), two amino acids (e.g., PP), three amino acids (e.g., APP), four amino acids (e.g., NAPP (SEQ ID NO: 352)), five amino acids (e.g, ANAPP (SEQ ID NO: 353)), six amino acids (e.g., AANAPP (SEQ ID NO: 354)), seven amino acids (e.g., PAANAPP (SEQ ID NO: 355)), eight amino acids (e.g., TPAANAPP (SEQ ID NO: 356)), nine amino acids (e.g., LTPAANAPP (SEQ ID NO: 357)), or ten amino acids of RPPSNFTGSS (SEQ ID NO: 358) of RLTPAANAPP (SEQ ID NO: 359) and / or a C terminal spacer comprising one amino acid (e.g., R), two amino acids (e.g., RP), three amino acids (e.g., RPP), four amino acids (e.g., RPPS (SEQ ID NO: 360)), five amino acids (e.g., RPPSN (SEQ ID NO: 361)), six amino acids (e.g., RPPSNF (SEQ ID NO: 362)), seven amino acids (e.g., RPPSNFT (SEQ ID NO: 363)), eight amino acids (e.g., RPPSNFTG (SEQ ID NO: 364)), nine amino acids (e.g., RPPSNFTGS (SEQ ID NO: 365)), or ten amino acids of RPPSNFTGSS (SEQ ID NO: 366). In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence having a formula of P(N)x-E-P(C)y or (ii) the amino acid sequence having the formula of P(N)x-E-P(C)y, wherein E comprises an MHC-presentable peptide comprising the MHC- presentable peptide sequence as set forth in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), e.g., SEQ ID NO: 6, wherein the P(N)x is an optional N terminal spacer comprising at least one amino acid, the P(C)y is an optional C terminal spacer comprising at least one amino acid, and wherein x and y are the number of amino acids of the N terminal spacer andthe C terminal spacer, respectively. In some aspects, the N terminal spacer and C terminal spacer are naturally occurring sequences when linked to the 15mer described in Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B). Therefore, any length of MHC-presentable peptides can be generated by a combination of various N terminal spacers and C terminal spacers, based on the antigen sequences.

[0134] In some aspects, the disclosure is directed to a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 6. In some aspects, the MHC-presentable peptide in the amino acid sequence encoded by the nucleotide sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 6 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 9.

[0135] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 10, SEQ ID NO: 11, or SEQ ID NO: 12, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence encoded by the nucleotide sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 aminoacids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 10. In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 10 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 13.

[0136] In some aspects, the present disclosure comprises a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the least 8 amino acids of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 14. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 14 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 17.

[0137] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids,e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 18. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 18 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 21.

[0138] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 22. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 22 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentablepeptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 25.

[0139] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 26. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 26 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 29.

[0140] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 30. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO:30 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 33.

[0141] In some aspects, the present disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 34. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 34 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 37.

[0142] In some aspects, the disclosure provides acomposition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of sequence at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptidesequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 38. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 38 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, wherein the MHC- presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 41.

[0143] In some aspects, the present disclosure comprises a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 42. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 42 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 45.

[0144] In some aspects, the disclosure comprises a composion comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide whichcomprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 46. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 46 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 49.

[0145] In some aspects, the disclosure comprises a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 50, SEQ ID NO: 51, or SEQ ID NO: 52, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 50. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 50 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids,or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 53.

[0146] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 54. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 54 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence as set forth in SEQ ID NO: 57.

[0147] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 58. In some aspects, the MHC-presentable peptide in theamino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 58 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 61.

[0148] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 62, SEQ ID NO: 63, or SEQ ID NO: 64, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 62. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 62 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 65.

[0149] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids(or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 66. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 66 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 69.

[0150] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 70, SEQ ID NO: 71, or SEQ ID NO: 72, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 70. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 70 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 73.

[0151] In some aspects, the disclosure provides a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 74, SEQ ID NO: 75, or SEQ ID NO: 76, or (ii) the amino acid sequence comprising the MHC- presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 74. In some aspects, the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 74 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii). In some aspects, the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC- presentable peptide sequence set forth in SEQ ID NO: 77.

[0152] In some aspects, the composition comprises (i) a nucleotide sequence that encodes an amino acid sequence comprising one or more MHC-presentable peptides set forth in Table 2A or Table 2B, or (ii) the amino acid sequence comprising one or more MHC-presentable peptides set forth in Table 2A or Table 2B. In some aspects, any MHC-presentable peptides described herein, e.g., Table 1A or Table 1B (or for example, Table 2A (15mer) or Table 2B), are capable of inducing a tolerizing immune response against Type I diabetes in a subject in need thereof. Given the immunoprevalence of these MHC-presentable peptides in donors, including both healthy and T1D individauls that are positive for T1D HLA Class II risk alleles DQ2.5, DQ8, or DQ2.5 and DQ8, the amino acid sequences comprising these MHC-presentable peptides are recognized herein as T1D-risk-associated peptides. The present disclosure also provides compositions (e.g., pharmaceutical compositions) comprising one or more of such MHC-presentable peptides or nucleotide sequence encoding the MHC-presentable peptides.

[0153] In some aspects, one or more of the MHC-presentable peptides in the amino acid sequence is less than 36 amino acids, less than 35 amino acids, less than 34 amino acids, less than33 amino acids, less than 32 amino acids, less than 31 amino acids, less than 30 amino acids, less than 29 amino acids, less than 28 amino acids, less than 27 amino acids, less than 26 amino acids, less than 25 amino acids, less than 24 amino acids, less than 23 amino acids, less than 22 amino acids, less than 21 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, less than 12 amino acids, less than 11 amino acids, less than 10 amino acids, or less than 9 amino acids. In some aspects, all MHC-presentable peptides in the amino acid sequence is less than 35 amino acids, less than 34 amino acids, less than 33 amino acids, less than 32 amino acids.

[0154] In some aspects, one or more MHC-presentable peptides in the amino acid sequence consist of 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 amino acids, or 35 amino acids. In some aspects, all MHC- presentable peptides in the amino acid sequence consist of 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 aminio acids, or 35 amino acids.

[0155] In some aspects, one or more MHC-presentable peptides in the amino acid sequence have 8-35 amino acids, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 8-34, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 8-33, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15-33, 8-32, 9-32, 10- 32, 11-32, 12-32, 13-32, 14-32, 15-32, 8-31, 9-31, 10-31, 11-31, 12-31, 13-31, 14-31, or 15-31 amino acids. In some aspects, all MHC-presentable peptides in the amino acid sequence have 8-35 amino acids, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 8-34, 9-34, 10-34, 11-34, 12-34, 13- 34, 14-34, 15-34, 8-33, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15-33, 8-32, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 8-31, 9-31, 10-31, 11-31, 12-31, 13-31, 14-31, or 15-31 amino acids.

[0156] In some aspects, the amino acid sequence further comprises a second MHC-presentable peptide that is heterologous to the MHC-presentable peptide. In some aspects, the second MHC- presentable peptide is an MHC-presentable peptide disclosed herein. In some aspects the second MHC-presentable peptide is not disclosed herein. In some aspects, the second MHC-presentablepeptide is derived from an antigen selected from the group consisting of Chromogranin-A (CHGA), Carboxypeptidase A1(CPA1), C1orf127 protein (C1orf127), Early growth response protein 4 (EGR4), Glutamate decarboxylase 2 (GAD2), Vitamin D-binding protein (GC), Guanine nucleotide-binding protein G(s) subunit alpha isoform XLas (GNAS), Glucose-6-phosphatase 2 (G6PC2 (IGRP)), Insulin (INS), Potassium channel subfamily K member 16 (KCNK16), Kinesin- like protein KIF1A (KIF1A), Neuroendocrine convertase 2 (PCSK2), Pancreas / duodenum homeobox protein 1 (PDX1), Proton-coupled zinc antiporter SLC30A8 (SLC30A8), and any combination thereof.

[0157] In some aspects, the amino acid sequence further comprises a third MHC-presentable peptide, a fourth MHC-presentable peptide, a fifth MHC-presentable peptide, a sixth MHC- presentable peptide, a seventh MHC-presentable peptide, a ninth MHC-presentable peptide, a tenth MHC-presentable peptide, an 11thMHC-presentable peptide, a 12thMHC-presentable peptide, a 13thMHC-presentable peptide, a 14thMHC-presentable peptide, a 15thMHC-presentable peptide, a 16thMHC-presentable peptide, a 17thMHC-presentable peptide, an 18thMHC-presentable peptide, a 19thMHC-presentable peptide, a 20thMHC-presentable peptide, a 21stMHC-presentable peptide, a 22ndMHC-presentable peptide a 23rdMHC-presentable peptide, a 24thMHC-presentable peptide, a 25thMHC-presentable peptide, a 26thMHC-presentable peptide, a 27thMHC-presentable peptide, a 28thMHC-presentable peptide, a 29thMHC-presentable peptide, a 30thMHC-presentable peptide, a 31stMHC-presentable peptide, a 32ndMHC-presentable peptide, a 33rdMHC- presentable peptide, a 34thMHC-presentable peptide, a 35thMHC-presentable peptide, a 36thMHC-presentable peptide, a 37thMHC-presentable peptide, a 38thMHC-presentable peptide, a 39thMHC-presentable peptide, a 40thMHC-presentable peptide, a 41stMHC-presentable peptide, a 42ndMHC-presentable peptide, a 43rdMHC-presentable peptide, a 44thMHC-presentable peptide, a 45thMHC-presentable peptide, a 46thMHC-presentable peptide, a 47thMHC-presentable peptide, a 48thMHC-presentable peptide, a 49thMHC-presentable peptide, a 50thMHC-presentable peptide, a 51stMHC-presentable peptide, a 52ndMHC-presentable peptide, a 53rdMHC-presentable peptide, a 54thMHC-presentable peptide, or a 55thMHC-presentable peptide. In some aspects, any one of the additional MHC-presentable peptides comprises at least eight amino acids of one or more MHC-presentable peptide sequences in Tables 1A, 1B, 2A, 2B, and / or 3.

[0158] In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54,SEQ ID NO: 54, SEQ ID NO: 58, and / or SEQ ID NO: 62 in any order. In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, and / or SEQ ID NO: 65 in any order. In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 60, and / or SEQ ID NO: 66 in any order.

[0159] In some aspects, the amino acid sequence encoded by the nucleotide sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, and / or SEQ ID NO: 67 in any order.

[0160] Also contemplated is an amino acid sequence comprising variants of the MHC- presentable peptides, or a nucleotide sequence encoding the amino acid sequence. For example, an amino acid sequence, or a nucleotide sequence encoding the amino acid sequence, can comprise an MHC-presentable peptide that differs by 1, 2, or 3 amino acids (e.g., substitutions, insertions, or deletions) relative to an MHC-presentable peptide disclosed herein. In some aspects, a composition can comprise an amino acid sequence comprising an MHC-presentable peptide set forth in Tables 1 and / or 2, with the N-terminal or C-terminal amino acid deleted, or a nucleotide sequence encoding the amino acid sequence. Such variants can be derived from, for example, mutant forms of the respective antigens that may be present in the human population. It is understood, according to scientific literature and databases (Rammensee et al., 1999 (supra); Godkin et al., 1997 (supra)), that certain positions of MHC-presentable peptides are typically anchor residues forming a core sequence fitting to the binding groove of the MHC. Thus, a skilled person in the art would be able to modify the amino acid sequences of an MHC-presentable peptide disclosed herein, by maintaining the known anchor residues, and determine whether such variants maintain the ability to bind the MHC. Alternatively, the MHC anchor residues can be modified to improve binding of the peptide to the MHC, without affecting the remaining residues that interact with the cognate TCR. The amino acid sequences or nucleotide sequence encoding the amino acidsequence comprising the MHC-presentable peptides disclosed herein or their variants are useful for stimulating T cell immune responses in vitro, ex vivo, or in vivo.

[0161] In some aspects, the amino acid sequence encoded by the nucleotide sequence of the disclosure comprising an MHC-presentable peptide set forth in Table 1A, Table 1B, Table 2A, Table 2B and Table 3, or a variant of such MHC-presentable peptide, is no more than 35 amino acids, no more than 30 amino acids, no more than 25 amino acids, no more than 20 amino acids, no more than 19 amino acids, no more than 18 amino acids, no more than 17 amino acids, no more than 16 amino acids, no more than 15 amino acids, or no more than 14 amino acids, in length. In some aspects, the amino acid sequence encoded by the nucleotide sequence of the disclosure does not comprise more than 100 (e.g., more than 90, more than 80, more than 70, more than 60, more than 50, more than 40, more than 30, more than 25, more than 20, more than 19, more than 18, more than 17, more than 16, more than 15, more than 14, more than 13, more than 12, more than 11, more than 10, more than 9, or more than 8) contiguous amino acids of an antigen set forth in Tables 1A, 1B, 2A, 2B, and / or 3. In some aspects, the amino acid sequence encoded by the nucleotide sequence of the disclosure comprises at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 99%, or 100% of the entire length of the corresponding antigen.

[0162] In some aspects, an amino acid sequence encoded by the nucleotide sequence of the disclosure comprises two or more MHC-presentable peptides of the same antigen. In some aspects, the two or more MHC-presentable peptides are partially overlapping, and the amino acid sequence encoded by the nucleotide sequence of the disclosure comprises the entire sequences of the two or more MHC-presentable peptides aligned. In some aspects, the amino acid sequence encoded by the nucleotide sequence of the disclosure comprises an MHC-presentable peptide presentable by a class II MHC. In some aspects, the amino acid sequence encoded by the nucleotide sequence of the disclosure comprises a T cell MHC-presentable peptide presentable by a class I MHC. In some aspects, the amino acid sequence encoded by the nucleotide sequence of the disclosure comprises an MHC-presentable peptide presentable by a class II MHC and an MHC-presentable peptide presentable by a class I MHC. Without wishing to be bound by theory, it is contemplated that the MHC-presentable peptides of such peptide can be presented by both class I and class II MHC proteins, thereby capable of stimulating an immune response by both CD8+and CD4+T cells.

[0163] An amino acid sequence encoded by the nucleotide sequence of the disclosure may further comprise a moiety (e.g., an amino acid sequence) that improves one or more characteristics of the MHC-presentable peptide or its manufacture or function. For example, in some aspects, theamino acid sequence (or a nucleotide sequence encoding the same) further comprises an amino acid sequence (or a nucleotide sequence) that facilitates delivery of the MHC-presentable peptide into an APC. In some aspects, the amino acid sequence encoded by a nucleotide sequence of the disclosure comprises a cell penetrating peptide, which facilitates cell uptake in a manner that does not require a cell membrane protein. In some aspects, the amino acid sequence encoded by a nucleotide sequence of the disclosure comprises a lipidation moiety, for example, to improve the half-live of the amino acid sequence. Exemplary cell penetrating peptides are disclosed in the CPPsite 2.0 database (crdd.osdd.net / raghava / cppsite / ), which includes more than 1,000 unique cell penetrating peptides. In some aspects, the amino acid sequence encoded by a nucleotide sequence of the disclosure further comprises a binding moiety (e.g., an antibody or an antigen-binding fragment thereof) that targets an APC (e.g., professional APC). Exemplary targets of such binding moiety include CD11b, CD11c, CD18, CD24, CD1a, CD206, DC inhibitory receptor 2 (DCIR2), and DEC205. In some aspects, the amino acid sequence encoded by a nucleotide sequence of the disclosure further comprises a moiety that improves immunogenicity of the MHC-presentable peptide. For example, in some aspects, the amino acid sequence encoded by a nucleotide sequence of the disclosure further comprises a heat shock protein-binding motif (see WO2019210055A2). Amino acid sequences encoded by a nucleotide sequence of the disclosure can be synthesized by the translation machinery (optionally in combination of transcription machinery) of a cell either in the cell or in vitro. Alternatively, an amino acid sequence and / or a nucleotide sequence of the disclosure can be chemically synthesized. In some aspects, the amino acid sequence is modified or comprises a non-germline encoded peptide, for example, to comprise or mimic a post-translational modification (PTM) of the antigen protein when expressed in an APC. Modified amino acid sequence comprise, but are not limited, to post-translational modifications (PTMs) and other non- germline encoded peptides as reviewed in (Mannering et al., (2019) Diabetologia 62:351-356, Doyle et al., (2014) Autoimmunity 47:220-233), such as defective ribosomal products (Kracht et al., (2017) Nat Med 23:501-507), peptide fusions (Babon et al., (2016) Nat Med 22:1482-1487, Delong et al., (2016) Science 351:711-714), amino acid substitutions or changes such as arginine to citrulline or deamidation (Babon et al., (2016) Nat Med 22:1482-1487, McLaughlin et al.,(2016) Clin Exp Immunol 185:133-140) that have been shown to be antigenic MHC-presentable peptides in Type I diabetes or other T cell-based studies. Other modified peptides include vicinal disulfide bond (Mannering et al.,(2005) J Exp Med 202:1191-1197), glutamine to glutamic acid conversion (Lummel et al.,(2014) Diabetes 63:237-247), arginine to citrulline (Babon et al.,(2016) Nat Med 22:1482-1487, Azoury et al.,(2021) Diabetes 70:2879-2891), chlorination (Sidney et al.,(2018)BMC Immunol 19:12), oxidation (Sidney et al.,(2018) BMC Immunol 19:12), deamidation (Sidney et al.,(2018) BMC Immunol 19:12), alternative splicing (Jong et al.,(2013) Diabetologia 56:2651- 2658), carbonylation (Yang et al.,(2017) Antioxid Redox Signal 29:1415-1431), aspartic acid to isoaspartic acid (Doyle et al.,46:6-13), glycosylation (Mei et al.,(2020) Mol Cell Proteomics 19:1236-1247), or phosphorylation (Cobbold et al., Sci Transl Med. (2013) 5(203):203ra125).

[0164] The present disclosure provides a composition (e.g., pharmaceutical composition) comprising a plurality of different amino acid sequences or a plurality of different nucleotide sequences encoding the MHC-presentable peptides disclosed herein. In some aspects, the composition comprises two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 150 or more, 200 or more, or 300 or more different amino acid sequences comprising MHC-presentable peptides disclosed herein or nucleotide sequences encoding MHC-presentable peptides disclosed herein. In some aspects, the composition comprises 5-500, 5-400, 5-300, 5-200, 5-150, 5-100, 5-90, 5-80, 5- 70, 5-60, 5-50, 5-40, 5-30, 5-20, 5-10, 10-500, 10-400, 10-300, 10-200, 10-150, 10-100, 10-90, 10- 80, 10-70, 10-60, 10-50, 10-40, 10-30, 10-20, 20-500, 20-400, 20-300, 20-200, 20-150, 20-100, 20-90, 20-80, 20-70, 20-60, 20-50, 20-40, 20-30, 30-500, 30-400, 30-300, 30-200, 30-150, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-500, 40-400, 40-300, 40-200, 40-150, 40-100, 40- 90, 40-80, 40-70, 40-60, 40-50, 50-500, 50-400, 50-300, 50-200, 50-150, 50-100, 50-90, 50-80, 50-70, 50-60, 100-500, 100-400, 100-300, 100-200, 100-150, 150-500, 150-400, 150-300, 150- 200, 200-500, 200-400, or 200-300 different amino acid sequences comprising MHC-presentable peptides disclosed herein or a nucleotide sequence encoding MHC-presentable peptides disclosed herein. In some aspects, the composition comprises a first amino acid sequence comprising an MHC-presentable peptide presentable by a class II MHC and a second amino acid sequence comprising an MHC-presentable peptide presentable by a class II MHC, optionally wherein the first and second amino acid sequence are different. In some aspects, the composition comprises a first amino acid sequence comprising an MHC-presentable peptide presentable by a class II MHC and a second amino acid sequence comprising an MHC-presentable peptide presentable by a class I MHC, optionally wherein the first and second amino acid sequence are different. Without wishing to be bound by theory, it is contemplated that the MHC-presentable peptides in such composition can be presented by both class I and class II MHC proteins, thereby capable of stimulating an immune response by both CD8+and CD4+T cells.

[0165] In some aspects, a composition comprising a nucleotide sequence or an amino acid sequence disclosed herein, when presented by cognate MHC(s), is capable of stimulating a T cell response, for example, enhancing survival, proliferation, activation, and / or memory formation of one or more T cells, in a T cell population obtained from a subject (e.g., peripheral blood mononuclear cells from a human subject) under ex vivo or in vivo conditions. Where the cognate MHC is a class II MHC, the peptide is capable of stimulating a CD4+T cell response. The peptide- MHC complex can be a soluble complex, immobilized on a solid surface (e.g., bead or nanoparticle), or presented on the surface of an APC. Viability of T cells can be assessed by methods known in the art such as cell counting or dye exclusion assays (e.g., with trypan blue or propidium iodide). Clonal T cell proliferation can be assessed by methods known in the art such as carboxyfluorescein succinimidyl ester (CFSE) dilution assay, Ki-67 staining, tritiated thymidine incorporation, BrdU incorporation (see Gratzner, Science (1982) 218(4571):474-75), or quantitation of ATP levels (e.g., with CellTiter-Glo Cell Viability assay). T cell activation can be assessed by methods known in the art such as staining for cell surface markers (e.g., upregulation of CD69, CD27, CD137, CD154, CD25, CD44, or CD107a, or downregulation of CD62L or CCR7) or cytokines (e.g., IFNγ or TNFα) or detecting secretion of cytokine proteins (e.g., IFNγ or TNFα) or proteins associated with cytolytic activity (e.g., GranzymeB or Perforin). Memory T cell formation can be assessed by methods known in the art such as staining for cell surface markers (e.g., CD45RO, CD95, Sca1, CD62L, CD27, CD127, and CD44). In certain aspects, the composition is capable of enhancing survival, proliferation, activation, and / or memory formation of both CD8+and CD4+T cells.

[0166] In some aspects, the composition that is administered according to the disclosed methods further comprises an immunomodulator. Non-limiting examples of such immunomodulators are disclosed elsewhere herein.

[0167] Nucleic acids encoding for the amino acid sequence and MHC-presentable peptides disclosed herein can be useful for treating and preventing T1D in a subject. Where the peptides or polypeptides constitute a fragment of the complete antigen protein, such tolerogenic nucleic acid compositions are also known as minigene vaccines.

[0168] In some aspects, at least one nucleotide sequence of the composition encodes a plurality of different peptides. The nucleotide sequence can be engineered to insert protease cleavage sites and / or ribosomal skipping elements between the MHC-presentable peptides, such that the encoded MHC-presentable peptides are processed to produce separate MHC-presentable peptides. Such polynucleotide constructs, also called “strings,” are useful as tolerogenic compositions (see, e.g.,Velders et al., J. Immunol. (2001) 166:5366-73; Schubert et. al., Genome Medicine (2016) 8:9). Therefore, the term “string construct” or “string polynucleotide” used herein refers to a construct or a polynucleotide sequence that contains at least two MHC-presentable peptides and at least one cleavable linker between the two MHC-presentable peptides so that the translated product results in two MHC-presentable peptides separate from each other. The term “string polypeptide” or “string amino acid sequence” used herein refers to an amino acid sequence that can be translated by a string construct or a string polynucleotide, but those string amino acid sequences may not be the translated product of the string polynucleotide because the cleavable linker(s) may have been cleaved during the translation or right after the translation, and the amino acid sequences may now be two sequences, each comprising one MHC-presentable peptide. In some aspects, the composition comprises one or more polynucleotide constructs that encode one or more of the MHC-presentable peptides disclosed herein with one or more protease cleavage sites and / or ribosomal skipping elements between the MHC-presentable peptides. Both coding and non-coding strands can be incorporated into the composition. In some aspects, the string refers to a polynucleotide chain that encodes a plurality of the MHC-presentable peptides in tandem. In some aspects, the string encodes 2 to 100, 2 to 90, 2 to 80, 2 to 70, 2 to 60, 2 to 50, 2 to 40, 2 to 30, 2 to 20, 2 to 10, 10 to 100, 10 to 90, 10 to 80, 10 to 70, 10 to 60, 10 to 50, 10 to 40, 10 to 30, 10 to 20, 20 to 100, 20 to 90, 20 to 80, 20 to 70, 20 to 60, 20 to 50, 20 to 40, 20 to 30, 50 to 100, 50 to 90, 50 to 80, 50 to 70, or 50 to 60 peptides.

[0169] In some aspects, a string polynucleotide chain encodes a string amino acid sequence as disclosed in the following formula: E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10 (I); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11 (II); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 (III); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13 (IV); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14 (V); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14-L14-E15 (VI);E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14-L14-E15-L15-E16 (VII); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14-L14-E15-L15-E16-L16-E17 (VIII); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14-L14-E15-L15-E16-L16-E17-L17-E18 (IX); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14-L14-E15-L15-E16-L16-E17-L17-E18-L18-E19 (X); E1-L1-E2-L2-E3-L3-E4-L4-E5-L5-E6-L6-E7-L7-E8-L8-E9-L9-E10-L10-E11-L11-E12 -L12-E13-L13-E14-L14-E15-L15-E16-L16-E17-L17-E18-L18-E19-L19-E20 (XI); or E1-L1-E2-E3-L2-E4-L3-E5-L4-E6-E7-L5-E8-L6-E9-L7-E8-E9-L8-E10 (XII), wherein EN is an MHC-presentable peptide comprising at least eight amino acids of an MHC- presentable peptide sequence in Table 1A, Table 1B, or Table 2 (e.g., 31mers), LN is an optional linker, e.g., a cleavable linker, and N is any integer. Due to the cleavable linkers, after the translation, the amino acid sequence can be cleaved into multiple MHC-presentable peptides that can be processed and loaded onto an MHC complex. See. FIG. 1. In some aspects, each MHC- presentable peptide in the string amino acid sequence is unique (different from each other). In some aspects, all linkers are the same in the string amino acid sequence. In some aspects, some linkers are different from each other.

[0170] In some aspects, the composition comprises (i) a string nucleotide sequence that encodes an amino acid sequence comprising one MHC-presentable peptide comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 35 amino acids of one MHC-presentable peptide selected from the MHC- presentable peptides in Table 1A, Table 1B, Table 2A (15mer), or Table 2B (for example see Table 2A (19mer, 25mer, or 31mer) and Table 3)and another MHC-presentable peptide comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 35 amino acids of one MHC-presentable peptide selected from theMHC-presentable peptides in Table 1A, Table 1B, Table 2A (15mer), or Table 2B (for example see Table 2A (19mer, 25mer, or 31mer) and Table 3), or (ii) the amino acid sequence encoded by the string nucleotide sequence. In some aspects, the composition comprises (i) a string nucleotide sequence that encodes an amino acid sequence comprising at least three MHC-presentable peptides, at least four MHC-presentable peptides, at least five MHC-presentable peptides, at least six MHC-presentable peptides, at least seven MHC-presentable peptides, at least eight MHC- presentable peptides, at least ten MHC-presentable peptides, wherein at least one, two, three, four, five, six, seven, eight, nine, or ten of the MHC-presentable peptides comprieses at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, or at least 35 amino acids of one MHC-presentable peptide selected from the MHC-presentable peptides in Table 1A, Table 1B, Table 2A (15mer), or Table 2B (for example see Table 2A (19mer, 25mer, or 31mer) and Table 3).

[0171] In some aspects, the composition comprises (i) a string nucleotide sequence that encodes an amino acid sequence comprising about ten to about 30 MHC-presentable peptides (e.g., 10 to 20 MHC-presentable peptides, 10 to 25 MHC-presentable peptides, 15 to 20 MHC- presentable peptides, 15 to 25 MHC-presentable peptides, or 20 to 30 MHC-presentable peptides), wherein one or more, or all of the MHC-presentable peptides comprise at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, or at least 35 amino acids of the MHC-presentable peptides in Table 1A, Table 1B, Table 2A (15mer), or Table 2B (for example see Table 2A (19mer, 25mer, or 31mer) and Table 3).

[0172] In some aspects, the composition comprises (i) a string nucleotide sequence that encodes an amino acid sequence comprising about ten to about 30 MHC-presentable peptides (e.g., 10 to 20 MHC-presentable peptides, 10 to 25 MHC-presentable peptides, 15 to 20 MHC- presentable peptides, 15 to 25 MHC-presentable peptides, or 20 to 30 MHC-presentable peptides), wherein one or more, or all of the MHC-presentable peptides comprises at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, or at least 35 amino acids of the MHC-presentable peptides in Table 1A, Table 1B, Table 2A (15mer), or Table 2B (for example see Table 2A (19mer, 25mer, or 31mer) and Table 3).

[0173] In some aspects, the composition comprises (i) a string nucleotide sequence that encodes an amino acid sequence comprising about ten to about 30 MHC-presentable peptides (e.g.,10 to 20 MHC-presentable peptides, 10 to 25 MHC-presentable peptides, 15 to 20 MHC- presentable peptides, 15 to 25 MHC-presentable peptides, or 20 to 30 MHC-presentable peptides), wherein one or more of the MHC-presentable peptides comprise at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, or at least 35 amino acids of the MHC-presentable peptides in Table 1A, Table 1B, Table 2A (15mer), or Table 2B (for example see Table 2A (19mer, 25mer, or 31mer) and Table 3), and wherein one or more of the MHC-presentable peptides comprises a heterologous MHC-presentable peptide that is not disclosed herein, e.g., Table 1A, Table 1B, or Table 3. In some aspects, one or more of the heterologous MHC-presentable peptides are derived from an antigen known to be associated with T1D. In some aspects, one or more of the heterologous MHC-presentable peptides are derived from Chromogranin-A (CHGA), Carboxypeptidase A1(CPA1), C1orf127 protein (C1orf127), Early growth response protein 4 (EGR4), Glutamate decarboxylase 2 (GAD2), Vitamin D-binding protein (GC), Guanine nucleotide-binding protein G(s) subunit alpha isoform XLas (GNAS), Glucose-6-phosphatase 2 (G6PC2 (IGRP)), Insulin (INS), Potassium channel subfamily K member 16 (KCNK16), Kinesin-like protein KIF1A (KIF1A), Neuroendocrine convertase 2 (PCSK2), Pancreas / duodenum homeobox protein 1 (PDX1), Proton-coupled zinc antiporter SLC30A8 (SLC30A8), or any combination thereof.

[0174] In some aspects, the peptides are arranged on a string to maximize recognition by HLA- DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof. In some aspects the MHC- presentable peptide-coding sequences in a string construct are flanked by one or more sequences selected for better cleavability for peptide presentation by MHCs, better expression, and / or improved translation in a cell in a subject. The flanking sequences may comprise ribosomal skipping elements such as a T2A, P2A, F2A, or E2A sequence. In some aspects, the one or more cleavage sequences are selected from the group consisting of FRAC (SEQ ID NO: 367), KRCF (SEQ ID NO: 368), KKRY (SEQ ID NO: 369), ARMA (SEQ ID NO: 370), RRSG (SEQ ID NO: 371), MRAC (SEQ ID NO: 372), KMCG (SEQ ID NO: 373), ARCA (SEQ ID NO: 374), KKQG (SEQ ID NO: 375), YRSY (SEQ ID NO: 376), SFMN (SEQ ID NO: 377), FKAA (SEQ ID NO: 378), KRNG (SEQ ID NO: 379), YNSF (SEQ ID NO: 380), KKNG (SEQ ID NO: 381), RRRG (SEQ ID NO: 382), KRYS (SEQ ID NO: 383), and ARYA (SEQ ID NO: 384). In some aspects, the linker comprise any one of linkers in Table 4. In some aspects, the amino acid sequences encoded by a string construct further comprises a signal protein sequence.In some aspects the string constructs may be mRNA. In some aspects, a pharmaceutical composition may comprise one or more mRNA string constructs.

[0175] In some aspects, the tolerogenic composition is a DNA composition (e.g., tolerogenic DNA composition). The DNA composition may comprise a DNA plasmid or a minicircle DNA encoding for one or more antigen peptides and / or MHC-presentable peptides disclosed herein. The DNA plasmid can further comprise a promoter sequence and a backbone sequence. The DNA composition can be formulated with nano-carriers to shield the DNA composition from degradation by DNases and other enzymes. Suitable nano-carriers for DNA compositions are well known in the art and may include for example, nanoparticles, nanotubes, dendrimers, liposomes, foams, hydrogels, cubosomes, quantum dots, natural drug carriers, and exosomes.

[0176] Depending upon the circumstances, the DNA composition is administered to a patient by intravenous injection, oral, or pulmonary administration. Alternatively, the DNA composition can be applied topically via the skin or intramuscularly. Alternatively, the DNA composition can be administered by intramuscular (IM) injection, subcutaneous injection, or intradermal injection. Regardless of the injection site, the pDNA transfects cells in the subject, which can then undergo a type of programmed cell death known as apoptosis. A cell that undergoes apoptosis releases small membrane-bound fragments that known as apoptotic bodies, which trigger the endocytosis of cellular debris by immature dendritic cells (iDC). The activity of iDCs can then initiate the generation of exogenous antigens, which are exclusively presented by class II MHCs. In addition to acting on either myocytes or keratinocytes, an administration route can also transfect APCs located near the injection site. This direct transfection route results in endogenous transgene expression and presentation of the antigen peptide through both class I and class II MHCs, thereby yielding both CD8+ and CD4+ T cells.

[0177] In some aspects, the tolerogenic composition is an RNA composition (e.g., tolerogenic RNA composition) encoding for one or more antigen peptides and / or MHC-presentable peptides disclosed herein. In some aspects the RNA composition is a messenger RNA (mRNA) composition. The RNA composition optionally further comprises one or more chemical modifications. For example, the RNA composition can comprise a five-prime (5′) and a three- prime (3′) untranslated region (UTR), and can be further stabilized by 7-methylguanosine (m7G) 5′ cap and 3′ poly (A) tails respectively, and / or a suitable Poly(A) sequence. In some aspects, the mRNA composition comprises modified nucleosides, for example Pseudouridine (Ψ), N1- methylpseudouridine (m1Ψ), and 5-methylcytidine (m5C). In some aspects, the RNA composition comprises a self-amplifying RNA (saRNA), which further encodes an RNA-dependent RNApolymerase that can be translated in situ, thereby amplifying the peptide- or antigen-encoding sequence(s) in situ (see, e.g., Bloom et al., Gene Therapy (2021) 28:117–29). In some aspects, the mRNA composition can be formulated into delivery agents, including but not limited to lipid nanoparticles, polymers, liposomes, and peptides. An overview of mRNA compositions such as mRNA cancer vaccines is provided, for example, in Miao, L. et al., Molecular Cancer (2021) 20:41.

[0178] In some aspects, the tolerogenic composition comprises both an antigen peptide and a nucleic acid coding for the peptide. In some aspects, the antigen peptide and the nucleic acid are linked.

[0179] In some aspects, the pharmaceutical composition further comprises a delivery agent for delivering the nucleic acid(s) to a target cell (e.g., tolerogenic target cell). It is understood that the target cell, after internalizing the peptide(s), can present the peptide(s) on the cell surface with a cognate MHC (e.g., HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof), thereby to stimulate tolerogenic T cell responses. Delivery agents for delivering nucleic acids to target cell (e.g., tolerogenic target cell) include but are not limited to lipid nanoparticles (“LNPs”).

[0180] In some aspects, the delivery agent comprises an LNP. In some aspects, the lipid comprises a cationic lipid, e.g., a ionizable cationic lipid. In one aspect, the lipid forms a complex with and / or encapsulates the nucleic acid (e.g., RNA). Nanoparticulate RNA formulations with defined particle size in which the net charge of the particles is close to zero or negative, such as electroneutral or negatively charged lipoplexes of RNA and liposomes, for example, lipoplexes comprising DOTMA and DOPE or DOTMA and DOTMA and Cholesterol, can lead to substantial supply of RNA to the spleen's DCs after systemic administration. In some aspects, in a nanoparticulate RNA formulation, the ratio of positive charges to negative charges on the nanoparticles is 1.4:1 or less, and / or the zeta potential of the nanoparticles is 0 or less. In some aspects, the ratio of positive charges to negative charges in the nanoparticles is between 1.4:1 and 1:8, for example, between 1.2:1 and 1:4, between 1:1 and 1:3, between 1:1.2 and 1:2, between 1:1.2 and 1:1.8, between 1:1.3 and 1:1.7, between 1:1.4 and 1:1.6, or about 1:1.5. In some aspects, the zeta potential of the nanoparticles is -5 mV or less, -10 mV or less, -15 mV or less, -20 mV or less, or -25 mV or less. In some aspects, the zeta potential of the nanoparticle is -35 mV or greater, -30 mV or greater, or -25 mV or greater. In some aspects, the nanoparticles have a zeta potential of -50 to 0 mV, for example, -40 to 0 mV, -30 to -10 mV. In some aspects, positive charges are contributed by at least one cationic lipid present in the nanoparticles; negative charges are contributed by RNA and certain lipid components of the LNPs such as anionic helper lipids. Insome aspects, the nanoparticles comprise at least one helper lipid, such as a neutral lipid or an anionic lipid.

[0181] In some aspects, the nanoparticles are lipoplexes that comprise DOTMA and DOPE in a molar ratio of 10:0 to 1:9, for example, 8:2 to 3:7, or 7:3 to 5:5, and where the ratio of charges from positive charges in DOTMA to negative charges in RNA is 1.8:2 to 0.8:2, for example, 1.6:2 to 1:2, 1.4: 2 to 1.1:2, or about 1.2:2. In some aspects, the nanoparticles are lipoplexes that comprise DOTMA and cholesterol in a molar ratio of 10: 0 to 1:9, for example, 8:2 to 3:7 or 7:3 to 5:5, and where the ratio of charges from positive charges in DOTMA to negative charges in RNA is 1.8:2 to 0.8:2, for example, 1.6:2 to 1:2, 1.4:2 to 1.1:2, or approximately 1.2:2. In some aspects, the nanoparticles are lipoplexes that comprise DOTAP and DOPE in a molar ratio of 10:0 to 1:9, for example, 8:2 to 3:7 or 7:3 to 5:5, and where the ratio of charges from positive charges in DOTMA to negative charges in RNA is 1.8:2 to 0.8:2, for example, 1.6:2 to 1:2, 1.4:2 to 1.1:2, or approximately 1.2:2. In some aspects, the nanoparticles are lipoplexes that comprise DOTMA and DOPE in a molar ratio of 2:1 to 1:2, for example, 2:1 to 1:1, and in which the ratio of positive charges in DOTMA to negative charges in RNA is 1.4:1 or less. In some aspects, nanoparticles are lipoplexes that comprise DOTMA and cholesterol in a molar ratio of 2:1 to 1:2, for example, 2:1 to 1:1, and in which the ratio of positive charges in DOTMA to negative charges in RNA is 1.4:1 or less. In some aspects, nanoparticles are lipoplexes that comprise DOTAP and DOPE in a molar ratio of 2:1 to 1:2, for example, 2:1 to 1:1, and in which the ratio of positive charges in DOTAP to negative charges in RNA is 1.4:1 or less.

[0182] In some aspects, the composition (e.g., LNP composition) further comprises an immunomodulator, such as an immunomodulator described elsewhere herein.

[0183] In some aspects, the tolerogenic nucleic acid composition further comprises one or more carriers or excipients. Exemplary excipients are described herein.

[0184] Nucleic acid compositions comprising such adjuvants, carriers, and / or excipients can be formulated by well-known conventional methods. These pharmaceutical compositions can be administered to the subject at a suitable dose. It is preferred that the pharmaceutically acceptable carrier be one which has no detrimental side effects or toxicity under the conditions of use. Preferably, a tolerogenic nucleic acid composition is sterile and produced according to GMP guidelines.

[0185] In some aspects, the tolerogenic composition is in the form of a lyophilized formulation or an aqueous solution. The tolerogenic composition can be in dosages suspended in any appropriate pharmaceutical carrier in sufficient volume to carry the dosage. Generally, the finalvolume, including carriers, adjuvants, and the like, typically will be at least 0.5 mL. The upper limit is governed by the practicality of the amount to be administered, generally in the range of 0.5 mL to about 4.0 mL, such as 0.5 mL to about 2.0 mL. In some aspects, the tolerogenic composition is administered to a patient enterally or parenterally. In some aspects, the tolerogenic compositions are administered to a patient by intravenous, intramuscular, intratumoral, intradermal, intrajejunal, intraileal, intracolonic, or intrarectal administration. Soluble pMHC Complexes

[0186] The present disclosure also provides a protein complex comprising a peptide disclosed herein complexed with a cognate MHC (e.g., HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof). In some aspects the peptide, the cognate MHC, and the complex thereof, are soluble. Where the MHC is a class II MHC (e.g., HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof), in some aspects, the protein complex comprises α1 domain and β1 domain of the class II MHC. In some aspects, the protein complex further comprises α2 domain and β2 domain of the class II MHC.

[0187] In some aspects, the amino acid sequence is fused with at least one polypeptide of the class II MHC (e.g., HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof). In some aspects, the first and second flexible linkers are peptide linkers, such that the single-chain construct can be produced recombinantly.

[0188] In some aspects, the amino acid sequence and / or the MHC (e.g., as a single-chain construct) is fused with a multimerization domain so as to form a multimer (e.g., dimer, trimer, tetramer, pentamer, or hexamer). Without wishing to be bound by theory, it is contemplated that the multimerization increases the avidity of the pMHC, thereby to compensate for the often low affinity of pMHCs to cognate TCRs. In addition to targeting T cells in vivo, such multimer can be used to probe T cells or isolated TCRs to identify a TCR that binds the MHC-presentable peptide. In some aspects, the multimerization domain comprises avidin or a variant thereof (e.g., streptavidin). In some aspects, the complex further comprises a barcode, for example, a barcode nucleic acid conjugated with a biotin that binds a streptavidin that is fused with the peptide and / or MHC. A pMHC multimer can comprise a plurality of the same pMHC. Alternatively, it can comprise a plurality of different pMHCs, e.g., two or more copies of a first pMHC and two or more copies of a second, different pMHC. In some aspects, the multimerization domain comprises an antibody (e.g., IgG, IgM, IgA) Fc region or a fragment thereof that mediates multimerization. In some aspects, the multimerization domain is a dimerization domain comprising an IgG (e.g., IgG4)Fc region or a fragment thereof that mediates dimerization (e.g., CH3 domain) (see Suarez et al., Transfus. Med. Hemother. (2020) 47:464–71). In some aspects, the multimerization domain comprises an IgM Cµ4 constant region or IgA Cα3 constant region, and optionally further comprises a corresponding tailpiece region (see, e.g., International Application No. PCT / US2022 / 023898). In some aspects, the multimerization domain comprises a Cµ2, Cµ3, and Cµ4 domain of IgM. In some aspects, the multimer further comprises an IgM tailpiece region. In some aspects, the multimer further comprises a J-domain, optionally wherein the J-domain can be fused with an immunomodulator. Exemplary immunomodulators are described in the “Presentation Agents” subsection below. In some aspects, the immunomodulator comprises a PD- 1 agonist, for example, an extracellular fragment of PD-L1 or an anti-PD-1 agonistic antibody or an antigen-binding fragment thereof.

[0189] In some aspects, the soluble pHMC (e.g., a single-chain construct) is linked to (e.g., fused with) an effector that reduces survival, proliferation, activation, and / or memory formation of one or more cytotoxic T cells. The soluble pMHC targets the effector to T cells that bind the pMHC, thereby specifically directing the effector’s function to such T cells. Non-limiting examples of suitable effectors include checkpoint protein agonists, anti-inflammatory cytokines, and cell death- inducing agents. For example, in some aspects, the effector comprises PD-L1 (e.g., Domain 1 or full extracellular domain), an agonistic antibody that binds PD-1, TIGIT, CTLA4, TIM-3, LAG-3, LILRB1, or LILRB2, or a binding domain or portion (e.g., an antigen-binding fragment) of any of these antibodies. In some aspects, the effector comprises a TNF receptor superfamily agonist (e.g., a TNF family molecule), such as CD137L, an anti-CD137 agonistic antibody, or an antigen- binding fragment thereof. In some aspects, the effector comprises HLA-G or an extracellular fragment thereof. In some aspects, the effector comprises an anti-inflammatory cytokine such as TGFβ or IL-10, which promotes Treg phenotype and context-dependent immunosuppression effects. In some aspects, the effector comprises an inducer of cell death. For example, in some aspects, the inducer of cell death is a TNF receptor superfamily agonist, such as FasL, an anti-Fas agonistic antibody or an antigen-binding fragment thereof, TRAIL, an agonistic anti-DR4 or anti- DR5 antibody or an antigen-binding fragment thereof. In some aspects, the inducer of cell death is a cytotoxic agent such as a microtubule inhibitor or DNA damaging agent. It is contemplated that two or more such effector moieties, either separately or conjugated or fused together, may be linked to the soluble pMHC.Tolerizing Vaccine

[0190] In some aspects, the present disclosure comprises a tolerizing vaccine composition that is capable of inducing antigen-specific immune tolerance to treat autoimmune diseases, e.g., T1D. In some aspects, a tolerizing vaccine composition comprises a nucleotide sequence that encodes one or more MHC-presentable peptides derived from one or more antigens specific to a tissue or the amino acid sequence comprising the one or more MHC-presentable peptides, wherein the tissue represents the primary site of a disease or disorder, wherein the presentability of the MHC- presentable peptides in a risk-associated or highly prevalent HLA for the disease or disorder are experimentally measured or predicted. In some aspects, the presentability is determined by MEDi, NetMHC, Mass Spectrometry, or any combination thereof, as disclosed elsewhere herein. Methods of Inducing Tolerizing Immune Response

[0191] In some aspects, the disclosure comprises a method of inducing a tolerizing immune response against Type I Diabetes in a subject, comprising administering a nucleotide sequence that encodes an amino acid sequence comprising one or more MHC-presentable peptides to the subject, wherein at least one of the MHC-presentable peptides are specific to HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof. In some aspects, the tolerizing immune response is against Type I diabetes.

[0192] In some aspects, the immune response comprises (i) an induction of antigen-specific T cell tolerance, (ii) an increase in Treg cells (e.g., CD4+ Treg cells or FOXP3+ Treg cells), (iii) inhibition of autoimmunity, (iv) an induction of anergy of effector T cells, (e.g., CD4+ T effector cells), (v) inhibition of cytokine production, (vi) a decrease in a pro-inflammatory cytokine, (vii) an increase in an immunosuppressive cytokine, (viii) a suppression of CD8+ effector cells, (ix) an increase of LAG3+ CD49b+ Type 1 Regulatory (Tr1) cells, or any combination thereof. In some aspects, the immune response comprises an increase in the number of Treg cells, e.g., FOXP3+ Treg cells. In some aspects, the immune response comprises an increase in the number of Tr1 cells, e.g., LAG3+CD49b+ Tr1 cells. In some aspects, the immune response comrprises an increased activation of Treg and / or Tr1 cells, e.g., increased cytokine production by Treg cells.

[0193] In some aspects, the immune response comprises a decrease of a pro-inflammatory cytokine, wherein the pro-inflammatory cytokine comprises Interferon γ, Interferon beta-1a, Interferon alpha, (all subtypes), Interleukin-1 alpha, Interleukin-1 beta, Interleukin-2, Interleukin- 6, Interleukin-8, Interleukin-12, Interleukin-17, Interleukin-18, Interleukin-23, Tumor Necrosis Factor-α, Granulocyte-macrophage colony-stimulating factor, or any combination thereof.

[0194] In some aspects, the immune response comprises an increase of an immunosupressive cytokine, wherein the immunosupressive cytokine comprises Interleukin-1Ra, Interleukin-4, Interleukin-10, Interleukin-11, Interleukin-13, Transforming Growth Factor-β, Interleukin-33, Interleukin-35, Interleukin-37, or any combination thereof.

[0195] In some aspects, the present disclosure provides a method of inducing a tolerizing immune response in a subject in need thereof, comprising administering to the subject a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide disclosed herein, e.g., one or more MHC-presentable peptides as set forth in Tables 1A, 1B, 2A, 2B, and / or 3, or (ii) the amino acid sequence comprising the MHC- presentable peptide. In some aspects, the present disclosure provides a method of inducing a tolerizing immune response in a subject in need thereof, comprising administering to the subject a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide as set forth in Tables 1A, 1B, 2A, 2B, and / or 3, or (ii) the amino acid sequence comprising the MHC-presentable peptide.

[0196] In some aspects, the present disclosure provides a method of inducing a tolerizing immune response in a subject in need thereof, comprising administering to the subject a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide disclosed herein, e.g., one or more MHC-presentable peptides as set forth in Tables 1A, 1B, 2A, 2B, and / or 3, or (ii) the amino acid sequence comprising the MHC- presentable peptide, wherein the MHC-presentable peptide is specific to HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof. In some aspects, the present disclosure provides a method of inducing a tolerizing immune response in a subject in need thereof, comprising administering to the subject a composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide as set forth in Tables 1A, 1B, 2A, 2B, and / or 3, or (ii) the amino acid sequence comprising the MHC-presentable peptide, wherein the MHC-presentable peptide is specific to HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof.

[0197] In some aspects, the composition that is administered according to the disclosed methods further comprises an immunomodulator. Non-limiting examples of such immunomodulators are disclosed elsewhere herein.Methods of Treating T1D

[0198] The present disclosure provides methods of treating T1D comprising administering a therapeutically effective amount of a pharmaceutical composition, tolerogenic composition, or APC, e.g., aAPC, disclosed herein to a subject in need thereof.

[0199] It is contemplated that the therapies disclosed herein are useful in treating symptomatic or pre-symptomatic T1D. T1D disease progression is characterized by several stages of the disease that are characterized by a gradual loss of β-cell function over time. Stages include pre-stage 1, stage 1, stage 2, and stage 3. It is appreciated, however, that not all stages are present in all patients. In pre-stage 1, exposure to driving factors creates the conditions for β-cell autoimmunity to emerge. In stage 1, β-cell autoantibodies are persistent, but normoglycemia remains and there are no clinical symptoms. Throughout stage 2, the number of β-cell autoantibodies may induce dysglycemia but still without any diabetes symptoms. In stage 3, β-cell autoantibodies are predominant and clear symptoms of diabetes have emerged. As the disease progresses, β-cell function falls below the threshold required to maintain glucose control creating a requirement for insulin replacement therapy. Genetic and environmental risk are both included in the disease etiology.

[0200] T1D can be diagnosed by various methods. For example, the glycated hemoglobin (A1C) test measures the percentage of blood sugar attached to the oxygen-carrying protein in red blood cells (hemoglobin). The higher the blood sugar levels, the more hemoglobin has sugar attached. An A1C level of 6.5 percent or higher on two separate tests indicates diabetes. Additionally, random blood and fasting blood sugar tests can be performed. A blood sample is taken at a random time and may be confirmed by repeat testing. Blood sugar values are expressed in milligrams per deciliter (mg / dL) or millimoles per liter (mmol / L). Regardless of the last meal, a random blood sugar level of 200 mg / dL (11.1 mmol / L) or higher suggests diabetes, especially when coupled with any of the signs and symptoms of diabetes, such as frequent urination and extreme thirst. For the fasting blood sugar test a blood sample will be taken after an overnight fast. A fasting blood sugar level less than 100 mg / dL (5.6 mmol / L) is normal. A fasting blood sugar level from 100 to 125 mg / dL (5.6 to 6.9 mmol / L) is considered prediabetes. If the blood sugar level is 126 mg / dL (7 mmol / L) or higher on two separate tests, suggests diabetes. Additional autoantibody tests (for example for Islet Cell Cytoplasmic Autoantibodies (ICA), Glutamic Acid Decarboxylase Autoantibodies (GADA), Insulinoma-Associated-2 Autoantibodies (IA-2A), Insulin Autoantibodies (IAA) and / or Zinc Transporter-8 Autoantibodies (ZnT8)) can confirm T1D.

[0201] The methods and compositions described herein can be used alone or in combination with other therapeutic agents and / or modalities. The term administered “in combination,” as used herein, is understood to mean that two (or more) different treatments are delivered to the subject during the course of the subject’s affliction with the disorder, such that the effects of the treatments on the patient overlap at a point in time. In some aspects, the delivery of one treatment is still occurring when the delivery of the second begins, so that there is overlap in terms of administration. This is sometimes referred to herein as “simultaneous” or “concurrent delivery.” In some aspects, the delivery of one treatment ends before the delivery of the other treatment begins. In some aspects of either case, the treatment is more effective because of combined administration. In some aspects, delivery is such that the reduction of a symptom, or other parameter related to the disorder is greater than what would be observed with one treatment delivered in the absence of the other. The effect of the two treatments can be partially additive, wholly additive, or greater than additive.

[0202] The disclosure provides a method of treating T1D in a subject by the administration of a second therapeutic agent in combination with one or more of the therapies disclosed herein. Exemplary second therapeutic agents that may be used as part of a combination therapy, include, for example, subcutaneous injections of insulin combined with continuous glucose monitoring technology, insulin / glucagon delivery systems such as an artificial pancreas, metformine, pramlitide, glucagon-like peptide-1 receptor agonists (GLP-RAs) combined with insulin, sodium- glucose co-transporter inhibitors (SGLTi), tissue transplants, gene therapy, stem-cell therapies, and nutrition therapy.

[0203] The amount of the tolerogenic composition or artificial APC therapy disclosed herein and the amount of the additional therapeutic agent, and the relative timing of administration, may be selected in order to achieve a desired combined therapeutic effect. For example, when administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, simultaneously, or together. Further, for example, the tolerogenic composition or artificial APC therapy may be administered during a time when the additional therapeutic agent(s) exerts its prophylactic or therapeutic effect, or vice versa. Methods of Identifying MHC-presentable peptides

[0204] In some aspects, the present disclosure provides a method of identifying an MHC- presentable peptide that is capable of inducing a tolerizing immune response in a subject in needthereof, comprising selecting an MHC-presentable peptide that is specific to HLA-DQ2.5. In some aspects, the disclosure provides a method of identifying an MHC-presentable peptide that is capable of inducing a tolerizing immune response in a subject in need thereof, comprising selecting an MHC-presentable peptide that is specific to HLA-DQ8. In some aspects, the disclosure provides a method of identifying an MHC-presentable peptide that is capable of inducing a tolerizing immune response in a subject in need thereof, comprising selecting an MHC-presentable peptide that is specific to (or presentable by) HLA-DRB1. In other aspects, the disclosure provides a method of identifying an MHC-presentable peptide that is capable of inducing a tolerizing immune response in a subject in need thereof, comprising selecting an MHC-presentable peptide that is presentable by both HLA-DQ2.5 and HLA-DQ8, both HLA-DQ2.5 and HLA-DRB1, both HLA- DQ8 and HLA-DRB1, or all three.

[0205] In some aspects, the being presented on MHC comprises expressing in a reporter cell line a recombinant MHC-MHC-presentable peptide complex comprising a covalently bound candidate peptide, detecting reporter cells that show surface expression of the MHC-MHC- presentable peptide complex, and determining the sequence of candidate MHC-presentable peptide presented at the cell surface. In some aspects, the selecting comprises excluding an MHC- presentable peptide highly presented on MHC. III. ANTIGEN-PRESENTING CELLS

[0206] In some aspects, the present disclosure provides an APC composition comprising one or more antigen-presenting cells (APCs) presenting or capable of presenting one or more MHC- presentable peptides disclosed herein. In some aspects, the APC is a tolerogenic APC. APCs and tolerogenic APCs

[0207] The present disclosure provides tolerogenic antigen-presenting cells (APCs) or a population or composition (e.g., pharmaceutical composition) thereof. APCs are a group of cells (e.g., immune cells) that mediate the cellular immune response by displaying endogenous and exogenous antigen complexed to major histocompatibility complexes (MHCs) class I and class II (“MHC I” and “MHC II”) on the cell surface for recognition by certain lymphocytes such as T cells. Tolerogenic APCs can be found in all tissues but are found in abundance in the skin, liver, spleen, and lymph nodes. In some aspects, the tolerogenic APC expresses scavenger receptor MARCO, ILT-3, ILT-4, and / or CD52.

[0208] APCs include professional APCs and non-professional APCs. Professional APCs include but are not limited to dendritic cells (DCs), macrophages, Langerhans cells, and B cells. Non-professional APCs include but are not limited to endothelial cells, fibroblasts, certain cells in the liver, and lymph node stromal cells that are capable of expressing MHC I and MHC II proteins and can present exogenous antigens. An APC can also be an artificial APC (e.g., drosophila cells) engineered to express an MHC that presents an MHC-presentable peptide. Also contemplated herein are artificial APCs, for example, a bead, nanoparticle, or liposome, that presents a peptide- MHC on the surface. artificial APCs can also be used to prime or stimulate T cells ex vivo or in vivo.

[0209] A function of dendritic cells (DCs) is to present antigens to T cells. Dendritic cells typically use two types of major histocompatibility complex (MHC) to display antigen peptides: MHC I and MHC II. MHC I trains CD8+ T-cells into cytotoxic, tumor-cell killers; and MHC II trains CD4+ T-cells into cytokine-producing helper cells. Clinical and pre-clinical data suggest that both T-cell types help to kill tumors. The peptides presented by MHC I and MHC II are not necessarily the same between each other, or between patients.

[0210] Immature dendritic cells (iDCs) are characterized by high endocytic activity and low T-cell activation potential. Immature dendritic cells phagocytose pathogens and degrade their proteins into small pieces and upon maturation present those fragments at their cell surface using MHC molecules. Simultaneously, iDCs upregulate cell-surface receptors that act as co-receptors in T-cell activation such as CD80 (B7.1), CD86 (B7.2), and CD40, greatly enhancing their ability to activate T-cells. Once iDCs have come into contact with a presentable antigen, iDCs become activated and mature into mature dendritic cells (mDCs), which in turn, can activate helper T-cells and cytotoxic T-cells as well as B-cells by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals.

[0211] Tolerogenic DCs (tolDCs) comprise several subsets of cells, for example VitD3-tolDC, Rapa-DC, DC10, Dex-tolDC, and ATDC. TolDCs induce tolerance via several contact-dependent and contact-independent mechanisms. TolDCs are generally characterized by low expression of costimulatory molecules (CD80, CD86, and CD83), upregulation of inhibitory and modulatory receptors, secretion of low pro-inflammatory and high levels of anti-inflammatory cytokines. TolDCs present antigens through normal T cell TCR and DC MHC interactions. However, mature tolerogenic DCs express high levels of CD86, which stimulates CD28 signaling to stabilize Treg cells (see Halliday et al., Front. Immunol. (2020) 11:600000). In some aspects, a tolDC is generated by loading or pulsing an immature dendritic cell (iDC) in vitro with apoptotic bodies from a cellthat expresses an autoantigen and / or presents an MHC-presentable peptide thereof (e.g., one or more MHC-presentable peptides disclosed herein) (see Marin-Gallen et al., Clin. Exp. Immunol. (2010) 160(2): 207–14). In some aspects, a tolDC is generated by loading or pulsing an iDC in vitro with one or more MHC-presentable peptides of an autoantigen (e.g., one or more MHC- presentable peptides disclosed herein) and culturing the iDC under immunosuppressive conditions. Exemplary immunosuppressive conditions include but are not limited to presence of an agonist of an immune checkpoint protein (e.g., an agonistic anti-CTLA-4 antibody or an antigen-binding fragment thereof conjugated to an anti-CD11c antibody or an antigen-binding fragment thereof for coating the iDC). Interaction tolDCs with T cells leads to inhibition of effector T cell responses and the induction of regulatory T cells (Tregs).

[0212] In some aspects, the target cell is a tolerogenic target cell in the spleen, such as a marginal zone macrophage, a metallophilic macrophage, or a marginal zone dendritic cell. Marginal zone dendritic cells (Langerin+CD8+DC) reside in the splenic marginal zone and are important for the regulation of tolerance toward cell-associated self-antigens. Markers for marginal zone DCs include CD8 and CD103.

[0213] In some aspects, dendritic cells can be generated in vivo or ex vivo from monocytes, sometimes referred to as monocyte-derived dendritic cells. Briefly, monocytes can transition from CD14+CD83- monocytes to CD14-CD83- immature DCs under the influence of IL-4 and GMCSF and then upregulate CD83 upon activation / maturation to become CD14-CD83+ mDC (see, e.g., Putz et al., Methods Mol Med. (2005) 109:71-82). In general, the transition from immature to mature DC is not instantaneous and requires some time, during which time the DCs undergo a maturing process. Some DCs may mature faster than others and thus, the population may be a mix of immature, maturing, semi-mature, and mature DCs, while the population as a whole is in the process of maturing.

[0214] Monocyte-derived dendritic cells (moDC) can also be generated in vitro from peripheral blood mononuclear cells (PBMCs). Plating of PBMCs in a tissue culture flask permits adherence of monocytes. Treatment of these monocytes with interleukin 4 (IL-4) and granulocyte- macrophage colony stimulating factor (GM-CSF) leads to differentiation to immature dendritic cells. Subsequent treatment with tumor necrosis factor (TNF), IL-6, IL-1β, and / or PGE2 further differentiates the iDCs into mature DCs.

[0215] Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death.There are three main groups of macrophages, classically-activated (M1) macrophages, wound- healing macrophages (also known as alternatively-activated (M2) macrophages), and regulatory macrophages (Mregs). Regulatory macrophages (Mregs) can provide a tolerogenic environment. Marginal zone macrophages (MZM or MZMϕ) and metallophilic macrophages (MMMϕ) are a subset of specialized splenic macrophages that interact with apoptotic material entering the spleen from circulation. Hepatic macrophages comprise a heterogeneous population of cells, for example, Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. Hepatic macrophages can be tolerogenic antigen-presenting cells that inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Markers for macrophages include CD11b / Integrin alpha M, CD14, CD68, Fc gamma RIII / CD16, Fc gamma RI / CD64, and CCR5.

[0216] In some aspects, the target cell is a tolerogenic target cell in the liver, such as a liver sinusoidal endothelial cell (LSEC), MARCO+Kupffer cell, or a monocyte-derived macrophage. LSECs are in direct contact with blood and possess efficient endocytic pathways for exogenic antigen endocytosis. Markers for LSECs include CD31, CD36, stabilin 1, 2, and B1, lipoprotein receptor-related protein-1, and certain C-type lectin receptors. For example, Type 1 LSEC are CD36hiCD32−CD14−LYVE-1−, while Type 2 LSEC are LYVE- 1+CD32hiCD14+CD54+CD36mid-lo. LSECs are not only able to present exogenous antigen on MHC II but also on MHC I and are capable of antigen cross-presentation to CD8+T cells. LSECs can upregulate the co-inhibitory molecule B7-H1 in CD8+T-cells, and shift the balance from activation to tolerance induction in CD8+T-cells. Naïve CD4+T-cells primed by LSECs under steady state can differentiate into regulatory T-cells (Tregs) that lack the transcription factor Forkhead-Box-Protein P3 (FoxP3), which is normally expressed by Tregs generated by professional APCs. LSEC-induced CD25lowFoxP3−T-cells are immune suppressive.

[0217] Hepatocytes are liver cells that can present exogenic antigens on MHC I and, in inflammatory conditions, MHC II molecules. Recently, hepatocytes were shown to be capable of priming naïve CD8+T-cells directly and via cross-presentation and of activating CD4+T-cells leading to the generation of CD4+CD25+FoxP3+Tregs (reviewed in Mehrfeld et al., Front. Immunol. (2018) 9:635). Markers for hepatocytes include KRT8 and KRT18.

[0218] Lymph node stromal cells (LNSC) are a group of cells that include, for example, fibroblastic reticular cells, and lymphatic and blood endothelial cells. LNSCs can promote a tolerogenic CD4+ T cell compartment and can aid in the deletion of antigen-specific CD8+ T cells. Markers for LNSCs comprise podoplanin (gp38) and PECAM-1 (CD31). Lymphatic endothelialcells have a high endocytic capacity, are capable of presenting exogenous antigens to T-cells on both MHC-I and MHC-II molecules, and mediate the deletion of autoreactive CD8+ T-cells.

[0219] In some aspects, the APC is an artificial APC, for example, a cell line engineered to express an MHC (see Turtle et al., Cancer J. (2010) 16(4): 374–81). In some aspects, the cell line is a lymphoblast cell line (e.g., K562). aAPCs are designed to mimic the temporal and spatial aspects of T cell-APC interactions. Such artificial APCs can be used to activate T cells (e.g., Treg cells) that express a cognate TCR in vitro or in vivo. Peptide loading

[0220] In some aspects, the APC composition disclosed herein is prepared by loading cells (e.g., monocytes and / or dendritic cells) with a composition disclosed herein, using the preloading method and / or the direct loading method.

[0221] Methods for peptide loading on APCs are known in the art, for example as described in WO2020 / 055931. Briefly, APCs such as monocytes, iDCs, and other non-mature DCs can be loaded with antigen peptides for presenting the incorporated MHC-presentable peptides on the cell surface. In a “preloading” method, monocytes and / or immature DCs are induced to internalize and proteolytically process the antigen peptides into shorter fragments (MHC-presentable peptides) for subsequent loading onto class I and class II MHCs and presentation to T cells. The processed antigen peptides may be stored by the monocytes and / or immature DCs during the differentiation and / or maturation process and subsequently presented on the surface of mature DCs. In some aspects, monocytes are incubated in the presence of one or more peptides prior to and / or during differentiation. In some aspects, immature DCs are incubated in the presence of one or more peptides prior to and / or during maturation. Alternatively, in a “direct loading” method, peptides can be directly loaded onto mature DCs. These peptides are directly loaded on the cell surface MHCs and are generally not shortened by intracellular processing. In some aspects, preloading of immature DCs and direct loading of mature DCs can be combined, resulting in a mixed population of pre-loaded and directly loaded mature DCs.

[0222] Alternatively, the APC composition disclosed herein can be prepared by nucleic acid transfection. For example, in some aspects, the APCs are prepared by transfecting a population of cells ex vivo with one or more nucleic acids encoding an antigen or a portion thereof (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the antigen). Nucleic acids useful herein include DNA and RNA (e.g., mRNA), including modified forms thereof. In some aspects, the nucleic acids transfected comprise mRNA, optionally mRNA havingone or more chemical modifications. Nucleic acid compositions described herein are also contemplated for use in this ex vivo transfection method.

[0223] In some aspects, the APCs of the APC composition are derived from a single subject and thus, as a population, express up to two variants from the two alleles of each MHC genetic locus (e.g., HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, HLA-DR). In other aspects, the APCs of the APC composition are pooled from a plurality of subjects and thus have greater MHC diversity.

[0224] In some aspects, the APCs of the APC composition present one or more MHC- presentable peptides disclosed herein. In some aspects, the APCs (e.g., APCs derived from a single subject) present a plurality of different MHC-presentable peptides disclosed herein. In some aspects, the APCs (e.g., APCs derived from a single subject) present two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, 15 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, or 100 or more different MHC-presentable peptides disclosed herein. In some aspects, the APCs (e.g., APCs derived from a single subject) present 5-100, 5-90, 5-80, 5-70, 5-60, 5-50, 5-40, 5-30, 5-20, 5-10, 10-100, 10-90, 10-80, 10-70, 10-60, 10-50, 10-40, 10-30, 10-20, 20-100, 20-90, 20-80, 20-70, 20-60, 20-50, 20-40, 20-30, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30- 40, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60- 90, 60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100 different MHC-presentable peptides disclosed herein. In some aspects, the APCs present a first MHC-presentable peptide by a class I MHC and a second MHC-presentable peptide by a class II MHC. Without wishing to be bound by theory, it is contemplated that such APCs are capable of stimulating an immune response by both CD8+and CD4+T cells.

[0225] In some aspects, at least 30, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the APCs in the APC composition present one or more MHC-presentable peptides disclosed herein. In some aspects, the percentage of lymphocytes (e.g., T cells) relative to all cells in the APC composition is 20% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In some aspects, the APC composition is substantially free of lymphocytes (e.g., T cells). In certain aspects, lymphocytes (e.g., T cells) are removed from the APC composition, for example, by surface marker-based magnetic bead selection or cell sorting.

[0226] In some aspects, the composition comprises an immunomodulator disclosed herein. It is contemplated that the immunomodulator may induce or stabilize a tolerogenic phenotype of the APC. IV. T CELLS

[0227] In some aspects, the present disclosure provides a T cell composition comprising one or more T cells (e.g., regulatory T cells) that recognize one or more MHC-presentable peptides presented by HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof on an APC (e.g., artificial APC), e.g., MHC-presentable peptides as set forth in Tables 1A, 1B, 2A, 2B, and / or 3.

[0228] It is understood that T cell activation (priming) and expansion requires two signals. TCR engagement with an MHC presenting a cognate peptide is the first step and is termed “signal 1.” After initial activation by signal 1, T cells can be expanded by providing “signal 2,” which can be provided by, for example, the B7 family proteins B7.1 and B7.2 which interact with CD28, or the tumor necrosis factor receptor (TNFR) family ligands OX-40L, CD70, 4-1BBL, which interact with OX-40, CD27, and 4-1BB on the T cell, respectively. Certain signal 2 interactions can be inhibitory to T cell expansion and effector function, such as the interaction of CTLA-4 with B7.1 or PD-1 with PD-L1 (B7.H1) or PD-L2 (B7-DC). Methods for T cell priming and expansion are known in the art, e.g., co-culturing the lymphocyte-rich fraction of the PBMCs with the APCs disclosed herein to expand T cells that are reactive to the MHC-presentable peptides disclosed herein. In some aspects, the APCs loaded with MHC-presentable peptides disclosed herein and prepared in accordance with the methods disclosed herein can be used to prime and expand certain T cells populations in vitro, ex vivo, and in vivo. CD4+and CD8+Regulatory T Cells

[0229] T cells are characterized by the expression of certain cell surface molecules such as the T cell receptor (TCR), a multiprotein complex that is involved in MHC binding. In some aspects, the T cells are derived from blood, bone marrow, lymphoid organs (e.g., lymph nodes or spleen), or tumor biopsies from a subject. These cells typically are primary cells, such as those isolated directly from a subject and / or tissue isolated from a subject. Other exemplary sources of T cells include T cell derived from stem cells, such as multipotent and pluripotent stem cells, including induced pluripotent stem cells (iPSCs). Stem cells can be directly isolated from a subject such as from cord blood, blood, or tissue. iPSCs can be derived from any cell type that can be used toproduce iPSCs. iPSCs can also be derived from a cell bank, and used to generate an allogeneic T cell product.

[0230] The T cells disclosed herein can be from a T cell subpopulation defined by function, activation state, maturity, potential for differentiation, expansion, recirculation, localization, and / or persistence capacities, antigen specificity, type of antigen receptor, presence in a particular organ or compartment, marker or cytokine secretion profile, and / or degree of differentiation. Included within this subpopulation of T cells are, for example, CD4+T cells and CD8+T cells.

[0231] Regulatory T (Treg) cells are a specialized subpopulation of T cells that act to suppress immune response, thereby maintaining homeostasis and self-tolerance. Tregs are able to inhibit T cell proliferation and cytokine production and play a critical role in preventing autoimmunity. Treg cells can be CD4+Treg cells or CD8+Treg cells.

[0232] Accordingly, CD4+ T cells are now commonly divided into two distinct lineages: CD4+Treg cells and CD4+conventional T helper (Th) cells. Conventional Th cells control the adaptive immunity by activating, in an antigen-specific fashion, other effector cells such as CD8+ cytotoxic T cells, B cells and macrophages. CD4+Treg cells are defined as CD4+T cells in charge of suppressing potentially deleterious activities of Th cells. Therefore, in some aspects, the present composition is capable of increasing a population of CD4+Treg cells.

[0233] Molecular markers are essential tools for defining and for analyzing a subpopulation of immune cells. The most widely used markers for Treg cells are CD4, CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR), lymphocyte activation gene-3 (LAG-3), CD127, and forkhead / winged-helix transcription factor box P3 (Foxp3).

[0234] The Foxp3 transcription factor is considered the most reliable marker for Treg cells. Tissue distribution analysis has shown that Foxp3 is mostly present in lymphoid tissues. The expression of Foxp3 is highly restricted to αβ T cells, and almost undetectable in B cells, γδ T cells, natural killer (NK) cells, macrophages and dendritic cells (DC). The expression of Foxp3 is mostly restricted to CD4+ T cells, but some CD8+ T cells do express Foxp3 as well.

[0235] Foxp3 is essential for T-cell functions and defective Foxp3 leads to lethal immune dysregulation. It has been suggested that Foxp3 may act as a repressor of transcription with the function of regulating the amplitude of the response of CD4+ T cells to activation. It has also been proposed that all human CD4+ and CD8+ T cells may upregulate Foxp3 and acquire suppressive properties upon activation. Genome-wide analysis has shown that Foxp3 binds to the promoter region of 700–1100 genes, many of those genes being associated with TCR signalling. A largenumber of Foxp3-bound genes were up- or down-regulated in Foxp3+ T cells, indicating that Foxp3 may act as both a transcriptional activator and repressor.

[0236] Treg cells, like all CD4+ T cells, possess a somatically-rearranged TCR, which allows specific recognition of antigenic peptides in the context of MHC class II molecules. Activation of conventional Th cells requires specific antigen recognition by the TCR and one would expect Treg cells to follow the same rule.

[0237] Concerning the antigen specificity of the CD4+Treg cell itself, in vitro experiments have demonstrated that CD4+Treg cells need to be first activated via the TCR to become suppressive. This implies that (1) CD4+Treg-cell activation is antigen-specific; and (2) the suppressive activity of CD4+Treg cells is triggered in an antigen-specific fashion. The same requirement for antigen seems to apply for Treg functions in vivo, since the proliferation of CD4+Treg cells in lymph nodes was shown to be antigen-dependent. In the non-obese diabetic mouse model for type 1 diabetes, CD4+Treg cells specific for a pancreatic autoantigen were much more efficient at preventing diabetes than polyclonal Treg cells. It was further shown that pancreas- specific Treg cells could only prevent diabetes when the Treg antigen was present in vivo in the pancreas. Finally, destructive autoimmune gastritis could be prevented by transfer of stomach- specific Treg cells, but not with polyclonal Treg cells.

[0238] Concerning the antigen specificity of the conventional Th cell that is suppressed by the CD4+Treg cell, the question is whether the Treg cell and the Th cell need to recognize the same antigen or not. In vitro mixed-cultures experiments have demonstrated that CD4+Treg cells activated by their cognate antigen can suppress the proliferation of conventional Th cells with different antigen specificities. In vivo, there is also evidence that CD4+Treg cells may suppress Th cells with other antigen specificities.

[0239] It has been proposed that Treg cells, which are in charge of maintaining self-tolerance, would be self-reactive. Supporting this hypothesis, self-reactive Treg cells have been observed in various mouse models for autoimmune diseases. For instance, Treg cells specific for the insulin B chain or for a pancreatic islet autoantigen protected against type 1 diabetes.

[0240] CD8+Treg cells possess important immunosuppressive functions. They can target antigen-activated CD4+helper T cells with their cytotoxic activity, thereby suppressing the activity of the CD4+helper T cells. Further, CD8+Treg cells can function by secreting various inhibitory cytokines and chemokines, including IL-10, transforming growth factor (TGF)-β, IL-16, IFN-γ and chemokine (C-C motif) ligand 4, that can render APCs tolerogenic. Depending on the history of a cell, subpopulations of CD8+Treg cells are characterized by several surface markers. In humans,the most prevalent are CD8+CD28–Treg cells that exhibit age-dependent accumulation in human and sub-populations of CD8+CD122+CD49d+T reg cells that express both PD-1 and IL-10 and suppress alloantigen-induced transplant rejections. CD8+Treg cells can be primed and / or expanded by induction of CD8+T cells, preferably naïve CD8+ T cells or natural regulatory CD8+ T cells, in vitro. Conditions for priming and / or expanding CD8+Treg cells include but are not limited to TGF-β and IL-2, or IL-15 and IL-2, in the presence of APCs or anti-CD3 / CD28 antibodies. Tolerogenic small molecules, such as rapamycin, cyclosporin A, methylprednisolone, or tacrolimus, can also be included in the cell culture for priming and / or expanding CD8+Treg cells.

[0241] In some aspects, the present disclosure provides a population of T cells that recognize one or more MHC-presentable peptides disclosed herein. In some aspects, the T cells include one or more subsets of T cells, such as a whole T cell population, CD8+cells, CD4+cells, or subpopulations and combinations thereof.

[0242] The T cells can be harvested from blood, bone marrow, lymphoid organs (e.g., lymph nodes), or tumor biopsies from a subject. In some aspects the T cells are harvested from a cell culture. The T cells can be purified before further culturing and expansion or can be used in a mixture with other cells. In some aspects, the primary T cells and stem cell derived T cells can be used fresh or frozen. The T cells can be maintained in ex vivo culture in the presence of one or more cytokines, such as IL-15 and / or IL-12, and optionally one or more of IL-21, IL-7, IL-2, IL- 10, and IL-6.

[0243] Also provided herein are populations of T cells reactive to the MHC-presentable peptides disclosed herein and compositions containing such T cells. In some aspects, a composition or population disclosed herein is enriched for such T cells. For example, in some aspects, at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the total cells in the composition or population recognize one or more MHC- presentable peptides disclosed herein. In some aspects, at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the CD8+ cells in the composition or population recognize one or more MHC-presentable peptides disclosed herein. In some aspects, at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the CD4+ cells in the composition or population recognize one or more MHC-presentable peptides disclosed herein.

[0244] Also provided herein are cell compositions comprising the T cells disclosed herein. In some aspects, the cell composition has been enriched for T cells (e.g., CD4+Treg cells). The enrichment can produce a composition in which at least 70%, at least 80%, at least 90%, at least95%, or at least 99% of the cells in the composition are T cells (e.g., CD4+Treg cells). In some aspects, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% of the T cells in the population are reactive to one or more MHC-presentable peptides of the selected antigens. T Cell Priming

[0245] In some aspects, the T cells (e.g., CD8+Treg cells) disclosed herein express endogenous TCRs that bind one or more MHC-presentable peptides disclosed herein. The T cells can be prepared by priming with an APC presenting the MHC-presentable peptides (e.g., an APC composition disclosed herein in Section III) ex vivo or in vivo.

[0246] T cells can be obtained from a blood sample of a subject (e.g., a patient) by apheresis. In some aspects, a lymphocyte-rich fraction and a monocyte-rich fraction can be acquired by elutriating peripheral blood mononuclear cells (PBMCs) of the subject. The monocyte-rich fraction can then be used to prepare antigen-presenting cells (APCs) for priming T cells, which can be obtained from the lymphocyte-rich fraction. In some aspects, the APC composition used for priming T cells is derived from the same subject as the T cells.

[0247] In some aspects, the APCs prepared in accordance with a method disclosed herein can be used to prime and expand T cells directed to the one or more selected antigen ex vivo, the method comprising co-culturing of the APCs with the T cells.

[0248] In some aspects, a lymphocyte-rich fraction of PBMCs can be co-cultured with the tolerogenic APCs disclosed herein (e.g., at a ratio between about 1:1 to about 40:1) to expand T cells that are reactive to the one or more MHC-presentable peptides. T cells directed to the one or more MHC-presentable peptides presented on the APCs preferentially expand and enrich during the co-culturing process, resulting in a primed and expanded T cell composition directed to the one or more MHC-presentable peptides. In certain aspects, the T cell composition may be re-stimulated by the same population of antigen-pulsed APCs. In some aspects, the T cell composition may be re-stimulated by another population of APCs pulsed by the same antigens or peptides (e.g., a fresh population of APCs produced by the same method as those used in initial stimulation).

[0249] In some aspects, the primed and expanded Treg cells are CD8+ CD122hiCD49d / f+, CD8+ CD28-, CD8+ CD103+ CD25hi, CD8+ FOXP3+, CD8+ FOXP3+ Helios+, or CD8+ CD45RClow. The resulting expanded and primed T cells can be used for various purposes (e.g., in T cell therapies as further disclosed herein).V. PHARMACEUTICAL COMPOSITIONS AND THERAPEUTIC METHODS

[0250] Disclosed herein are pharmaceutical compositions that contain one or more peptides, nucleic acids, APCs, T cells, or fusion proteins described herein that are useful for treating T1D. Exemplary pharmaceutical compositions described herein include but are not limited to peptide compositions, nucleic acid compositions, presentation agents (e.g., APCs and artificial APCs), and T cell compositions. Also disclosed are therapeutic uses of these pharmaceutical compositions. Tolerogenic Compositions

[0251] The T1D-associated MHC-presentable peptides disclosed herein or any nucleotide sequence encoding the MHC-presentable peptides are useful as tolerogenic compositions for treating and preventing T1D in a subject.

[0252] Accordingly, in one aspect, the present disclosure provides a pharmaceutical composition (e.g., tolerogenic composition) comprising one or more MHC-presentable peptides disclosed herein, an amino acid sequence encoding the MHC-presentable peptides, or one or more nucleotide sequences encoding the one or more MHC-presentable peptides or the amino acid sequence. Typically, the MHC-presentable peptide(s) are delivered to a target cell. Accordingly, in some aspects, the pharmaceutical composition further comprises a vehicle, e.g., a delivery agent, for delivering the T1D-associated peptide(s) to a target cell (e.g., tolerogenic target cell), a pancreatic cell. It is understood that the target cell, after internalizing the peptide(s), can present the peptide(s) on the cell surface with a cognate MHC (e.g., HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof), thereby to stimulate tolerogenic T cell responses. Delivery agents for delivering peptides to target cell (e.g., tolerogenic target cell) include but are not limited to nanoparticles, liposomes, virus-like particles, and red blood cells. The delivery agent may also reduce susceptibility of the peptides to proteolytic degradation.

[0253] In some aspects, the delivery agent comprises a nanoparticle. In some aspects, the nanoparticle is a polymeric nanoparticle composed of poly(lactide-co-glycolide) (PLG or PLGA) (Jamison et al., J. Immunol. (2019) 203(1) 48:57), polylactic acid (PLA) (Ruan et al., J. Control Release (2018) 279: 306-315), or poly(ε-caprolactone) (PCL) (Kim et al., Polymers (Basel) (2019) 11(2): 288). In some aspects, the polymeric nanoparticle is an amphiphilic block copolymer where at least one block is hydrophobic and one block is hydrophilic and the block copolymer self- assembles in an aqueous solution. The amphiphilic block copolymer can be a di-block A-B, tri- block A-B-A or a graft copolymer and can form polymeric micelles. The hydrophobic portion of the block copolymer forms the core of micelles, while the hydrophilic portion forms the shell orthe corona. The commonly used hydrophilic blocks are poly(ethylene glycol), poly(N-vinyl pyrrolidine) (PVP), polysialic acid (PSA) (Lei et al., Chem Sci. (2021) 12(18):6449-6457), and poly (N-isopropyl acrylamide) (pNIPAAm) among others. Hydrophobic blocks can comprise poly(propylene oxide) (PPO), PCL, PLGA, poly(L-lactide), poly(L-lysine) (Luo et al., J. Control Release (2013) 170(2): 259-67) poly(L-aspartic acid) (pAsp) (Kagaya et al., Gene Ther (2012) 19(1): 61-9), and poly(L-histidine) (pHis) (Wu et al., Biomaterials (2013) 34(4):1213-22). In some aspects the nanoparticle is a phospholipid micelle, where the hydrophobic block of polymeric micelles can be short, phospholipid residues like disteroyl phosphatidyl ethanolamine (DSPE) conjugated chemically to hydrophilic blocks like mPEG to form mPEG-DSPE micelles (Banerjee et al., Nanomedicine (2013) 9(6):722-8; Kumar et al., ACS Infect Dis. (2019) 5(3): 443-453). Polymeric nanoparticles can be formed by the double emulsion or nanoprecipitation methods. In some aspects, the nanoparticle is a gold particle with a layer of thiol-poly-ethylene glycol (PEG) (Yeste et al., Sci Signal. (2016) 9(433): ra61). In certain aspects, the gold nanoparticle is 60 nm in diameter. In some aspects, the nanoparticle is a liposome or a nanoliposome prepared by the thin- film hydration or ethanol injection method (Kenison et al., Proc. Natl. Acad. Sci. (2020) 117(50): 32017-32028, WO2019 / 165436 A1). In some aspects, the nanoparticle comprises a polystyrene particle or a polystyrene microsphere. Peptides can be encapsulated within the nanoparticles either by passive loading through spontaneous self-assembly (Luo et al., J Control Release. (2013) 10:170(2):259-67, Kenison et al., Proc. Natl. Acad. Sci. (2020) 117(50): 32017-32028, Pujol- Autonell et al., PLoS One (2015) 10(6): e0127057), electrostatically attached to the nanocarrier through interaction of opposite charges on the antigen and nanoparticle, physically adsorbed to nanoparticles (US2018 / 0071376 A1) or can be covalently attached to nanoparticle surface using well-defined conjugation chemistries as described in Bioconjugate Techniques, 3rdedition by Greg T Hermanson, Academic Press Inc. 2013)(US 2019 / 0282707 A1). The nanoparticles may incorporate functional groups for further reaction. Functional groups include electrophiles or nucleophiles which can conveniently react with other molecules. Examples of nucleophiles are primary amines, thiols, and hydroxyl groups. Examples of electrophiles are succinimidyl esters, aldehydes, isocyanates, and maleimides (US2019 / 0282707A1, US 2020 / 0046816A1). Functional groups can be readily incorporated in the PEG moiety that is used to decorate or graft the surface of nanoparticles and antigens.

[0254] In some aspects, the nanoparticle has a diameter that makes the particle suitable for systemic, in particular parenteral, administration of nucleic acids or peptides, typically a diameter less than 1,000 nanometers (nm). In some aspects, the nanoparticle has a diameter of less than 600nm. In some aspects, the nanoparticle has a diameter of less than 400 nm. In some aspects, the nanoparticle has a diameter in the range of 50 to 1,000 nm, for example, 50 to 900 nm, 50 to 800 nm, 50 to 700 nm, 50 to 600 nm, 50 to 500 nm, 50 to 400 nm, 50 to 300 nm, 50 to 200 nm, 50 to 100 nm, 100 to 1,000 nm, 100 to 900 nm, 100 to 800 nm, 100 to 700 nm, 100 to 600 nm, 100 to 500 nm, 100 to 400 nm, 100 to 300 nm, 100 to 200 nm, 150 to 1,000 nm, 150 to 900 nm, 150 to 800 nm, 150 to 700 nm, 150 to 600 nm, 150 to 500 nm, 150 to 400 nm, 150 to 300 nm, 150 to 200 nm, 200 to 1,000 nm, 200 to 900 nm, 200 to 800 nm, 200 to 700 nm, 200 to 600 nm, 200 to 500 nm, 200 to 400 nm, 200 to 300 nm. In some aspects, the nanoparticle has a diameter in the range of 250 to 550 nm, 300 to 500 nm, or 200 to 400 nm.

[0255] Nanoparticles can be targeted to certain cells (e.g., tolerogenic cells) by various means. Tolerogenic APCs can be found in the liver and spleen. Accordingly, in some aspects, the nanoparticle preferentially targets the liver. In some aspects, the nanoparticle preferentially targets the spleen, for example, by having a negative zeta potential (see WO 2013 / 192532, US 2019 / 0282707 A1, Kranz et al., Nature (2016) 534(7607): 396-401). In some aspects, the nanoparticle comprises an apoptotic body surrogate (see WO2013 / 184976). In some aspects, the nanoparticle comprises one or more apoptotic signaling molecules selected from annexin-1, annexin-5, milk fat globule-EGF-factor 8 (MFG-E8), calreticulin, phosphatidylserine, CD47, oxidized LDL, Fas-ligand and TNF. In certain aspects, the nanoparticle can be targeted to immune cells based on its particle size (Thorp et al., Front Immunol.(2020) 11:945, US 2019 / 0282707 A1). In some aspects the nanoparticle has a particle size of at least 200 nm, which allows particles to accumulate predominantly in the red pulp of the spleen and preferentially interact with immune cells therein. A particle size of 200 nm has been shown to preferentially accumulate in late endosomal or lysosomal compartments, making them ideal for immunomodulatory properties, as cargo movement through the late endosomal compartment via intracellular endosomal receptors is an important step for engaging adaptive and innate immune processes (Rejman et al., Biochem J. (2004) 377(Pt 1): 159-69, Gleeson., Semin Cell Dev Biol. (2014)31: 64-72). In some aspects, the particle has a diameter in the range of 50-800 nm, for example, 50-700 nm, 50-600 nm, 50-500 nm, 50-400 nm, 50-300 nm, 50-200 nm, 50-150 nm, 50-100 nm, 50-90 nm, 50-80 nm, 50-70 nm, 50-60 nm, 100-800 nm, 100-700 nm, 100-600 nm, 100-500 nm, 100-400 nm, 100-300 nm, 100- 200 nm, 100-150 nm, 150-800 nm, 150-700 nm, 150-600 nm, 150-500 nm, 150-400 nm, 150-300 nm, 150-250 nm, 150-200 nm, 200-800 nm, 200-700 nm, 200-600 nm, 200-500 nm, 200-400 nm, 200-300 nm.

[0256] In some aspects, the nanoparticle comprises a ligand (e.g., an antibody or an antigen- binding fragment thereof) that binds an antigen of a target cell (e.g., tolerogenic cell). In some aspects, the ligand comprises an antibody that binds such an antigen or an antigen-binding fragment thereof.

[0257] In some aspects, the delivery agent comprises a liposome. See, e.g., U.S. Patents Nos: 4,235,871; 5,000,887; 5,395,619; 4,837,028; U.S. Patent Applications Nos: US 2016 / 0324779A1, US 2020 / 0405642A1, and EP Patent No: EP3,095,440. Liposomes are lipid bilayer spherical membranes that provide both hydrophilic and hydrophobic environments. In some aspects, the liposome is a multilamellar liposomes / vesicles (MLV), an oligolamellar vesicles (OLV), a multilamellar liposomes / vesicles (MVV), or an unilamellar vesicles (ULV). In some aspects, the liposome comprises neutral lipids or negatively charged lipids. In some aspects, the liposome comprises dilaurylphosphotidylcholine (DLPC), dimyristoyl phosphotidylcholine (DMPC), dipalmitoylphosphotidylcholine (DPPC), dioleolylphosphotidyl choline (DOPC), dilaurylphosphotidylethanolamine (DLPE), dipalmitoylphosphotidylcholine (DPPC), distearoylphosphotidylcholine (DSPC), dioleolylphosphotidylcholine (DOPC), dimyristoyl phosphotidylethanolamine (DMPE), distearoylphosphotidylethanolamine (DSPE), dilaurylphosphotidylglycerol (DLPG), dicetylphosphate (DCP), dioleoylphosphatidylethanolamine (DOPE), 1,2-dioleoyl-3 trimethylammoniumpropane (DOTAP), dioleoylphosphatidylserine (DOPS), hydrogenated soybean phosphatidylcholine (HSPC), or cholesterol In some aspects, the liposome comprises PEG lipids. In some aspects, the liposome comprises L-α-egg phosphatidylcholine (EPC) and / or L-α-egg phosphatidylglycerol (EPG). In some aspects, the liposomes comprise 1,2-dioleoyl-sn-glycero3-phospho-L-serine (DOPS), 1,2-didodecanoyl-sn-glycero-3-phosphocholine (DLPC), and cholesterol. In some aspects, the liposomes are negatively charged.

[0258] In some aspects, the liposomes are nanoliposomes. In some aspects, the diameter of the liposome is 50-500 nm, for example, 50-400 nm, 50-300 nm, 50-200 nm, 50-100 nm, 100-500 nm, 100-400 nm, 100-300 nm, 100-200 nm, 200-500 nm, 200-400 nm, 200-300 nm, 300-500 nm, 300- 400 nm, or 400-500 nm.

[0259] Liposomes can be targeted to target cells (e.g., tolerogenic cells) by various means. In certain aspects, the liposome comprises phosphatidylserine. In certain aspects, the liposome comprises a ligand (e.g., an antibody an antigen-binding fragment thereof) that binds an antigen of a target cell (e.g., tolerogenic cell), as disclosed above in connection with nanoparticles.

[0260] In some aspects, the delivery agent comprises a targeting domain (e.g., a natural ligand, an antibody or an antigen-binding fragment thereof) that binds a receptor that is specifically or preferentially expressed on tolerogenic APCs, relative to immunogenic APCs. Exemplary receptors include but are not limited to MARCO, ILT-3, ILT-4, and CD52. Additional receptors comprise Clec9A, an anti-C-type lectin (e.g., DC-SIGN, Mannose receptor (MR), or macrophage galactose-type C-type lectin (MGL)), dendritic cell immunoreceptor (DCIR), DCIR2, DEC205 (CD205), Langerin (CD207), and Sialic-acid binding immunoglobulin-type lectin (Siglec).

[0261] In some aspects, the delivery agent comprises a erythroid cell such as a red blood cell. Erythroid cells can be engineered to include a wide variety of exogenous therapeutic proteins (see, e.g., WO 2019 / 133881). In some aspects, the erythroid cell is an enucleated mature red blood cell that lacks a nucleus. In some aspects, the erythroid cell is CD47-negative.

[0262] Tolerance to ingested antigens is an essential feature required for normal homeostasis and maintenance of barrier function in the gastrointestinal tract. Therefore, oral tolerance is another means of suppressing T cell immunity. In some aspects, the delivery agent comprises a carrier for delivering a peptide to the small intestine, for example, a coating that renders resistance to degradation in the low pH and the presence of proteolytic enzymes in the stomach. Also contemplated herein is a peptide composition suitable for oral administration without a delivery agent, for example, if the peptide is designed and / or chemically modified to resist degradation in the stomach.

[0263] In some aspects, the pharmaceutical composition (e.g., tolerogenic composition, nanoparticle composition, liposome composition, etc.) further comprises an immunomodulator or a nucleotide sequence encoding the immunomodulator. An immunomodulator can be an immunosuppressor, which reduces effector cell (e.g., cytotoxic T cell) activity, or an immunostimulator, which promotes T cell anergy or exhaustion (e.g., described in Kwong et al., Immunology & Cell Biology (2021) 99: 486–495, and Linsley et al., Curr Opin Endocrinol Diabetes Obes (2019) 26:213–218) It is contemplated that the immunomodulator, when delivered to or expressed by the target cell, may induce or stabilize a tolerogenic, anergic, or exhausted status of the target cell or a cell in the vicinity. In some aspects, the immunomodulator comprises an immunomodulatory cytokine, for example, an immunomodulatory cytokine selected from IL-2, IL-10, TGF-β, IL-37, IL-27, IL-35, IL-31, Vasoactive Intestinal Peptide (VIP), and variants thereof. In some aspects, the immunomodulatory cytokine is a mutant IL-2 that preferentially activates the IL-2Rαβγ receptor complex relative to the IL-2Rβγ receptor complex (see, e.g., Ghelani et al., Front. Immunol. (2020) 11:1106; Khoryati et al., Sci Immunol. (2020)5(50):eaba5264). In some aspects, the immunomodulator comprises a nucleic acid encoding an immunomodulatory cytokine. In some aspects, the immunomodulator comprises a nucleic acid encoding an intracellular or transmembrane immunomodulatory protein, for example, an immunomodulatory protein selected from PD-L1, PD-L2, ICOS ligand, ILT3, ILT4, BTLA, Fas, CD39, and indoleamine 2,3-dioxygenase 1 (IDO1), heme oxygenase 1, HLA-G, CD95L, galectin- 1, and DC-SIGN. In some aspects, the immunomodulator comprises an immunomodulatory compound, for example, an immunomodulatory compound selected from vitamin A, vitamin D (e.g., 1α,25-dihydroxyvitamin D3, a.k.a. calcitriol), adenosine, kynurenine, retinoic acid, rapamycin, dexamethasone, corticosteroids, and a AhR ligand such as 2-(1' H-indole-3'-carbonyl)- thiazole-4-carboxylic acid methyl ester (ITE). In some aspects, the immunomodulator provides a tolerogenic signal to an APC (e.g., dendritic cell, macrophage). In some aspects, the immunomodulator comprises a ligand (for example a carbohydrate ligand) or an antibody to APC receptors, for example, Clec9A, an anti-C-type lectin (e.g., DC-SIGN, Mannose receptor (MR), or macrophage galactose-type C-type lectin (MGL)), dendritic cell immunoreceptor (DCIR), DCIR2, DEC205 (CD205), Langerin (CD207), and Sialic-acid binding immunoglobulin-type lectin (Siglec). The immunomodulator can be delivered to the target cell by the delivery agent, for example, where the immunomodulator is present in or on the delivery agent. Depending on the form of the immunomodulator and delivery agent, the immunomodulator can be encapsulated or otherwise contained in the delivery agent, or covalently or non-covalently attached to an outer or inner surface of the delivery agent. In some aspects, the immunomodulator is disposed in the delivery agent.

[0264] In some aspects, the tolerogenic composition further comprises a pharmaceutically acceptable carrier, excipient, or stabilizer (see, e.g., Adeboye Adejare, Remington: The Science and Practice of Pharmacy (23d ed. 2020)). Suitable carriers are well known in the art and may include for example, nanoparticles, nanotubes, dendrimers, liposomes, foams, hydrogels, cubosomes, quantum dots, natural drug carriers, exosomes, and macrophages. Acceptable carriers, excipients, or stabilizers are nontoxic to the recipients at the dosages and concentrations, and may comprise phosphate buffered saline solutions, water, emulsions, such as oil / water emulsions, various types of wetting agents, and sterile solutions. In some aspects, the carrier or excipient comprises buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as Mercury((o-carboxyphenyl)thio)ethyl sodium salt (THIO E SAL), octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabenssuch as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as polyethylene glycol (PEG), TWEEN or PLURONICS.

[0265] Presently disclosed compositions comprising such carrier, excipients, or stabilizers can be formulated by well-known conventional methods. In some aspects, the tolerogenic composition is formulated to have a pH in the range of about 4.5 to about 9.0, including for example pH ranges of about any one of 5.0 to about 8.0, about 6.5 to about 7.5, or about 6.5 to about 7.0. In some aspects, the tolerogenic composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol. In some aspects, the tolerogenic composition is formulated as a liquid or the liquid is dried for a solid preparation (for example by spray drying or lyophilization). The lyophilization process is aimed at removal of water and typically involves freezing, primary drying, and secondary drying. To safeguard the peptide molecules from such stresses, typically cryoprotectants are used to improve viability and structural stability. Cryoprotectants include, but are not limited to DMSO, sugars like trehalose and sucrose, polysaccharides, like starch and dextran, or proteins. Solid preparations allow for a long storage time of the tolerogenic composition. Lyophilized preparations of the tolerogenic composition can be stored in bulk or in ready-made doses for use such as in a vial.

[0266] In some aspects, the pharmaceutical composition, e.g., a tolerogenic composition, is in the form of a lyophilized formulation or an aqueous solution. In some aspects, the pharmaceutical composition, e.g., a tolerogenic composition, is administered to a patient enterally or parenterally. Depending upon the circumstances, the tolerogenic composition can be administered to a patient by oral, sublingual, gastric, or rectal administration. Alternatively, the tolerogenic composition can administered to a patient by intravenous, intramuscular, intratumoral, intradermal, intrajejunal, intraileal, intracolonic, or intrarectal administration. The tolerogenic composition can be also delivered by subcutaneous axillary and / or inguinal injection. Presentation Agents

[0267] The T1D-associated peptides disclosed herein can be presented by cognate MHCs (e.g., HLA-DQ2.5, HLA-DQ8, HLA-DRB1, or any combination thereof) to form peptide-MHC(pMHC) complexes. The pMHC complexes bind T cells that are prevalent in T1D patients, and are thus useful for targeting T cells (e.g., Treg cells and Tr1 cells) for treating and preventing T1D in a subject. Given that pMHC complexes generally have low binding affinities to cognate T cell receptors (TCRs), a vehicle, e.g., a presentation agent, can be used to multimerize or cluster pMHC complexes to increase their binding avidity. Accordingly, in one aspect, the present disclosure provides a composition (e.g., pharmaceutical composition) comprising a plurality of pMHC complexes disclosed herein bound to a presentation agent. Useful presentation agents, when bound to the pMHC complexes, can form, e.g., antigen-presenting cells (APCs), artificial APCs,...

Claims

WHAT IS CLAIMED IS:

1. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in Table 1A or Table 1B, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC- presentable peptide sequence.

2. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide as set forth in Table 2A, Table 2B, or Table 3, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC- presentable peptide sequence.

3. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

4. The composition for use of any one of claims 1 to 3, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

6.

5. The composition for use of any one of claims 1 to 4, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ IDNO: 6 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

6. The composition for use of claim 3, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO:

9.

7. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 10, SEQ ID NO: 11, or SEQ ID NO: 12, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

8. The composition for use of any one of claims 1, 2, and 7, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

10.

9. The composition for use of any one of claims 1, 2, 7, and 8, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 10 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

10. The composition for use of claim 7, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO: 13.

11. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the least 8 amino acids of the MHC-presentable peptide sequence.

12. The composition for use of any one of claims 1, 2 and 11, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

14.

13. The composition for use of any one of claims 1, 2, 11, and 12, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 14 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

14. The composition for use of claim 11, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

17.

15. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

16. The composition for use of any one of claims 1, 2 and 15, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, atleast 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

18.

17. The composition for use of any one of claims 1, 2, 15 and 16, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 18 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

18. The composition for use of claim 15, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

21.

19. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

20. The composition for use of any one of claims 1, 2 and 19, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

22.

21. The composition for use of any one of claims 1, 2, 19, and 20, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 22 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

22. The composition for use of claim 19, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

25.

23. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

24. The composition for use of any one of claims 1, 2 and 23, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

26.

25. The composition for use of any one of claims 1, 2, 23, and 24, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 26 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

26. The composition for use of claim 23, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

29.

27. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consistsessentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

28. The composition for use of any one of claims 1, 2 and 27, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

30.

29. The composition for use of any one of claims 1, 2, 27, and 28, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 30 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

30. The composition for use of claim 27, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

33.

31. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

32. The composition for use of any one of claims 1, 2, and 31, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

34.

33. The composition for use of any one of claims 1, 2, 31, and 32, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 34 and further comprises (i) one amino acid, two amino acids, three aminoacids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

34. The composition for use of claim 31, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

37.

35. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of sequence at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

36. The composition for use of any one of claims 1, 2, and 35, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

38.

37. The composition for use of any one of claims 1, 2, 35, and 36, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 38 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

38. The composition for use of claim 35, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

41.

39. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequencecomprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

40. The composition for use of any one of claims 1, 2, and 39, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

42.

41. The composition for use of any one of claims 1, 2, 39, and 40, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 42 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

42. The composition for use of claim 39, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

45.

43. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

44. The composition for use of any one of claims 1, 2, and 43, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, atleast 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

46.

45. The composition for use of any one of claims 1, 2, 43, and 44, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 46 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

46. The composition for use of claim 43, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

49.

47. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 50, SEQ ID NO: 51, or SEQ ID NO: 52, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

48. The composition for use of any one of claims 1, 2, and 47, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

50.

49. The composition for use of any one of claims 1, 2, 47, and 48, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 50 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

50. The composition for use of claim 47, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

53.

51. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

52. The composition for use of any one of claims 1, 2, and 51, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

54.

53. The composition for use of any one of claims 1, 2, 51, and 52, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 54 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

54. The composition for use of claim 51, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

57.

55. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consistsessentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

56. The composition for use of any one of claims 1, 2 and 55, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

58.

57. The composition for use of any one of claims 1, 2, 55, and 56, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 58 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

58. The composition for use of claim 55, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO:

61.

59. A composition for use in inducing a tolerizing immune response in a subject in need thereof, the composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 62, SEQ ID NO: 63, or SEQ ID NO: 64, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

60. The composition for use of any one of claims 1, 2, or 59, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

62.

61. The composition for use of any one of claims 1, 2, 59, and 60, wherein the MHC- presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 62 and further comprises (i) one amino acid, two amino acids, three aminoacids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

62. The composition for use of claim 59, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO:

65.

63. The composition for use of any one of claims 1 to 62, wherein the MHC-presentable peptide in the amino acid sequence is less than 35 amino acids, less than 34 amino acids, less than 33 amino acids, less than 32 amino acids, less than 31 amino acids, less than 30 amino acids, less than 29 amino acids, less than 28 amino acids, less than 27 amino acids, less than 26 amino acids, less than 25 amino acids, less than 24 amino acids, less than 23 amino acids, less than 22 amino acids, less than 21 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, less than 12 amino acids, less than 11 amino acids, less than 10 amino acids, or less than 9 amino acids.

64. The composition for use of any one of claims 1 to 63, wherein the MHC-presentable peptide in the amino acid sequence consists of 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 amino acids, or 35 amino acids.

65. The composition for use of any one of claims 1 to 63, wherein the MHC-presentable peptide in the amino acid sequence has 8-35 amino acids, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 8-34, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 8-33, 9-33, 10-33, 11-33, 12-33, 13-33, 14- 33, 15-33, 8-32, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 8-31, 9-31, 10-31, 11-31, 12-31, 13-31, 14-31, or 15-31 amino acids.

66. The composition for use of any one of claims 1 to 65, wherein the amino acid sequence further comprises a second MHC-presentable peptide that is heterologous to the MHC-presentable peptide.

67. The composition for use of claim 66, wherein the amino acid sequence further comprises a third MHC-presentable peptide, a fourth MHC-presentable peptide, a fifth MHC-presentable peptide, a sixth MHC-presentable peptide, a seventh MHC-presentable peptide, a ninth MHC- presentable peptide, a tenth MHC-presentable peptide, an 11th MHC-presentable peptide, a 12th MHC-presentable peptide, a 13th MHC-presentable peptide, a 14th MHC-presentable peptide, a 15th MHC-presentable peptide, a 16th MHC-presentable peptide, a 17th MHC-presentable peptide, an 18th MHC-presentable peptide, a 19th MHC-presentable peptide, a 20th MHC- presentable peptide, a 21st MHC-presentable peptide, a 22nd MHC-presentable peptide a 23rd MHC-presentable peptide, a 24th MHC-presentable peptide, a 25th MHC-presentable peptide, a 26th MHC-presentable peptide, a 27th MHC-presentable peptide, a 28th MHC-presentable peptide, a 29th MHC-presentable peptide, a 30th MHC-presentable peptide, a 31st MHC- presentable peptide, a 32nd MHC-presentable peptide, a 33rd MHC-presentable peptide, a 34th MHC-presentable peptide, a 35th MHC-presentable peptide, a 36th MHC-presentable peptide, a 37th MHC-presentable peptide, a 38th MHC-presentable peptide, a 39th MHC-presentable peptide, a 40th MHC-presentable peptide, a 41st MHC-presentable peptide, a 42nd MHC- presentable peptide, a 43rd MHC-presentable peptide, a 44th MHC-presentable peptide, a 45th MHC-presentable peptide, a 46th MHC-presentable peptide, a 47th MHC-presentable peptide, a 48th MHC-presentable peptide, a 49th MHC-presentable peptide, a 50th MHC-presentable peptide, a 51st MHC-presentable peptide, a 52nd MHC-presentable peptide, a 53rd MHC- presentable peptide, a 54th MHC-presentable peptide, or a 55th MHC-presentable peptide.

68. The composition for use of any one of claims 1 to 67, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: 58, or SEQ ID NO:

62.

69. The composition for use of any one of claims 1 to 67, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, or SEQ ID NO:

65.

70. The composition for use of any one of claims 1 to 67, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 8, SEQ ID NO:12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 60, or SEQ ID NO:

66.

71. The composition for use of any one of claims 1 to 67, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, or SEQ ID NO:

67.

72. The composition for use of claim 1, wherein the MHC-presentable peptide is presentable by HLA-DQ2.5, HLA-DQ8, and / or HLA-DRB1.

73. The composition for use of claim 1, wherein the MHC-presentable peptide is specific to HLA-DQ2.

5.

74. The composition for use of claim 1, wherein the MHC-presentable peptide is specific to HLA-DQ8.

75. The composition for use of claim 1, wherein the MHC-presentable peptide is specific to HLA-DRB1.

76. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in Table 1A or Table 1B, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC- presentable peptide sequence.

77. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide as set forth in Table 2A, Table 2B, or Table 3, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC- presentable peptide sequence.

78. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide, which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: 8, or (ii) the amino acid sequence comprising the MHC-presentable peptide, which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

79. The composition of any one of claims 76 to 78, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

6.

80. The composition of any one of claims 76 to 79, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 6 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

81. The composition of claim 78, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO:

9.

82. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 10, SEQ ID NO: 11, or SEQ ID NO: 12, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

83. The composition of any one of claims 76, 77, and 82, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

10.

84. The composition of any one of claims 76, 77, 82 and 83, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 10 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

85. The composition of claim 82, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

13.

86. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 16, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the least 8 amino acids of the MHC-presentable peptide sequence.

87. The composition of any one of claims 76, 77, and 86, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

14.

88. The composition of any one of claims 76, 77, 86, and 87, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 14 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

89. The composition of claim 86, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

17.

90. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

91. The composition of any one of claims 76, 77, and 90, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

18.

92. The composition of any one of claims 76, 77, 90, and 91, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 18 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

93. The composition of claim 90, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

21.

94. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

95. The composition of any one of claims 76, 77, and 94, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

22.

96. The composition of any one of claims 76, 77, 94, and 95, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 22 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

97. The composition of claim 94, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

25.

98. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

99. The composition of any one of claims 76, 77, and 98, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

26.

100. The composition of any one of claims 76, 77, 98, and 99, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 26 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three aminoacids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

101. The composition of claim 98, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

29.

102. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 30, SEQ ID NO: 31, or SEQ ID NO: 32, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

103. The composition of any one of claims 76, 77, and 102, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

30.

104. The composition of any one of claims 76, 77, 102, and 103, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 30 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

105. The composition of claim 102, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

33.

106. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 34, SEQ ID NO: 35, or SEQ ID NO: 36, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consistsessentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

107. The composition of any one of claims 76, 77, and 106, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

34.

108. The composition of any one of claims 76, 77, 106, and 107, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 34 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

109. The composition of claim 106, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

37.

110. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of sequence at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide as set forth in SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

111. The composition of any one of claims 76, 77, and 110, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

38.

112. The composition of any one of claims 76, 77, 110, and 111, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 38 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine aminoacids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

113. The composition of claim 110, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

41.

114. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

115. The composition of any one of claims 76, 77, and 114, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

42.

116. The composition of any one of claims 76, 77, 114, and 115, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 42 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

117. The composition of claim 114, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

45.

118. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 46, SEQ ID NO: 47, or SEQ ID NO: 48,or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of the at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

119. The composition of any one of claims 76, 77, and 118, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

46.

120. The composition of any one of claims 76, 77, 118, and 119, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 46 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

121. The composition of claim 118, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

49.

122. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 50, SEQ ID NO: 51, or SEQ ID NO: 52, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

123. The composition of any one of claims 76, 77, and 122, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

50.

124. The composition of any one of claims 76, 77, 122, and 123, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 50 and further comprises (i) one amino acid, two amino acids, three amino acids, fouramino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

125. The composition of claim 122, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

53.

126. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

127. The composition of any one of claims 76, 77, and 126, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

54.

128. The composition of any one of claims 76, 77, 126, and 127, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 54 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

129. The composition of claim 126, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

57.

130. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in SEQ ID NO: 58, SEQ ID NO: 59, or SEQ ID NO: 60, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

131. The composition of any one of claims 76, 77, and 130, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

58.

132. The composition of any one of claims 76, 77, 130, and 131, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth in SEQ ID NO: 58 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

133. The composition of claim 130, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO:

61.

134. A composition comprising (i) a nucleotide sequence that encodes an amino acid sequence comprising an MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC- presentable peptide sequence as set forth in SEQ ID NO: 62, SEQ ID NO: 63, or SEQ ID NO: 64, or (ii) the amino acid sequence comprising the MHC-presentable peptide which comprises, consists essentially of, or consists of at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of the MHC-presentable peptide sequence.

135. The composition of any one of claims 76, 77, and 134, wherein the MHC-presentable peptide in the amino acid sequence comprises at least 9 amino acids, at least 10 amino acids, at least 11 amino acids, at least 12 amino acids, at least 13 amino acids, at least 14 amino acids, or at least 15 amino acids of the MHC-presentable peptide sequence as set forth in SEQ ID NO:

62.

136. The composition of any one of claims 76, 77, 134, and 135, wherein the MHC-presentable peptide in the amino acid sequence comprises the MHC-presentable peptide sequence set forth inSEQ ID NO: 62 and further comprises (i) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the N terminus, (ii) one amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids at the C terminus, or (iii) both (i) and (ii).

137. The composition of claim 134, wherein the MHC-presentable peptide in the amino acid sequence comprises, consists essentially of, or consists of the MHC-presentable peptide sequence set forth in SEQ ID NO:

65.

138. The composition of any one of claims 76 to 137, wherein the MHC-presentable peptide in the amino acid sequence is less than 35 amino acids, less than 34 amino acids, less than 33 amino acids, less than 32 amino acids, less than 31 amino acids, less than 30 amino acids, less than 29 amino acids, less than 28 amino acids, less than 27 amino acids, less than 26 amino acids, less than 25 amino acids, less than 24 amino acids, less than 23 amino acids, less than 22 amino acids, less than 21 amino acids, less than 20 amino acids, less than 19 amino acids, less than 18 amino acids, less than 17 amino acids, less than 16 amino acids, less than 15 amino acids, less than 14 amino acids, less than 13 amino acids, less than 12 amino acids, less than 11 amino acids, less than 10 amino acids, or less than 9 amino acids.

139. The composition of any one of claims 76-137, wherein the MHC-presentable peptide in the amino acid sequence consists of 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids, 16 amino acids, 17 amino acids, 18 amino acids, 19 amino acids, 20 amino acids, 21 amino acids, 22 amino acids, 23 amino acids, 24 amino acids, 25 amino acids, 26 amino acids, 27 amino acids, 28 amino acids, 29 amino acids, 30 amino acids, 31 amino acids, 32 amino acids, 33 amino acids, 34 amino acids, or 35 amino acids.

140. The composition of any one of claims 76-137, wherein the MHC-presentable peptide in the amino acid sequence has 8-35 amino acids, 9-35, 10-35, 11-35, 12-35, 13-35, 14-35, 15-35, 8-34, 9-34, 10-34, 11-34, 12-34, 13-34, 14-34, 15-34, 8-33, 9-33, 10-33, 11-33, 12-33, 13-33, 14-33, 15- 33, 8-32, 9-32, 10-32, 11-32, 12-32, 13-32, 14-32, 15-32, 8-31, 9-31, 10-31, 11-31, 12-31, 13-31, 14-31, or 15-31 amino acids.

141. The composition of any one of claims 76-140, wherein the MHC-presentable peptide amino acid sequence further comprises a second MHC-presentable peptide that is heterologous to the MHC-presentable peptide.

142. The composition of claim 141, wherein the amino acid sequence further comprises a third MHC-presentable peptide, a fourth MHC-presentable peptide, a fifth MHC-presentable peptide, a sixth MHC-presentable peptide, a seventh MHC-presentable peptide, a ninth MHC-presentable peptide, a tenth MHC-presentable peptide, an 11th MHC-presentable peptide, a 12th MHC- presentable peptide, a 13th MHC-presentable peptide, a 14th MHC-presentable peptide, a 15th MHC-presentable peptide, a 16th MHC-presentable peptide, a 17th MHC-presentable peptide, an 18th MHC-presentable peptide, a 19th MHC-presentable peptide, a 20th MHC-presentable peptide, a 21st MHC-presentable peptide, a 22nd MHC-presentable peptide a 23rd MHC- presentable peptide, a 24th MHC-presentable peptide, a 25th MHC-presentable peptide, a 26th MHC-presentable peptide, a 27th MHC-presentable peptide, a 28th MHC-presentable peptide, a 29th MHC-presentable peptide, a 30th MHC-presentable peptide, a 31st MHC-presentable peptide, a 32nd MHC-presentable peptide, a 33rd MHC-presentable peptide, a 34th MHC-presentable peptide, a 35th MHC-presentable peptide, a 36th MHC-presentable peptide, a 37th MHC- presentable peptide, a 38th MHC-presentable peptide, a 39th MHC-presentable peptide, a 40th MHC-presentable peptide, a 41st MHC-presentable peptide, a 42nd MHC-presentable peptide, a 43rd MHC-presentable peptide, a 44th MHC-presentable peptide, a 45th MHC-presentable peptide, a 46th MHC-presentable peptide, a 47th MHC-presentable peptide, a 48th MHC- presentable peptide, a 49th MHC-presentable peptide, a 50th MHC-presentable peptide, a 51st MHC-presentable peptide, a 52nd MHC-presentable peptide, a 53rd MHC-presentable peptide, a 54th MHC-presentable peptide, or a 55th MHC-presentable peptide.

143. The composition of any one of claims 76, 77 and 138 to 142, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 22, SEQ ID NO: 26, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 42, SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 54, SEQ ID NO: 54, SEQ ID NO: 58, or SEQ ID NO:

62.

144. The composition of any one of claims 76, 77 and 138 to 142, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 7, SEQ ID NO: 11, SEQ ID NO: 15, SEQ ID NO: 19, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 47, SEQ ID NO: 51, SEQ ID NO: 55, SEQ ID NO: 59, or SEQ ID NO:

65.

145. The composition of any one of claims 76, 77 and 138 to 142, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 8, SEQID NO: 12, SEQ ID NO: 16, SEQ ID NO: 20, SEQ ID NO: 24, SEQ ID NO: 28, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 48, SEQ ID NO: 52, SEQ ID NO: 56, SEQ ID NO: 60, or SEQ ID NO:

66.

146. The composition of any one of claims 76, 77 and 138 to 142, wherein the amino acid sequence comprises the MHC-presentable peptide sequences as set forth in SEQ ID NO: 9, SEQ ID NO: 13, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 49, SEQ ID NO: 53, SEQ ID NO: 57, SEQ ID NO: 61, or SEQ ID NO:

67.

147. The composition of any one of claims 76 to 146, wherein the MHC-presentable peptide is specific to HLA-DQ2.5, HLA-DQ8 and / or HLA-DRB1.

148. The composition of any one of claims 1 to 147, wherein the amino acid sequence induces a tolerizing immune response.

149. The composition for use of any one of claims 1 to 75 or composition of any one of claims 76 to 148, wherein the tolerizing immune response is against Type 1 Diabetes.

150. The composition for use of any one of claims 1 to 75 and 149 or composition of any one of claims 75 to 148, wherein the immune response comprises (i) an induction of antigen-specific T cell tolerance, (ii) an increase in Treg cells (e.g., CD4+ Treg cells or FOXP3+ Treg cells), (iii) inhibition of autoimmunity, (iv) an induction of anergy of effector T cells, (e.g., CD4+ T effector cells), (v) inhibition of cytokine production, (vi) a decrease in a pro-inflammatory cytokine, (vii) an increase in an immunosuppressive cytokine, (viii) a suppression of CD8+ effector cells, (ix) an increase of LAG3+ CD49b+ Tr1 cells, or any combination thereof.

151. The composition for use of any one of claims 1 to 75, 149, and 150 or the composition of any one of claims 75 to 149, wherein the immune response comprises an increase in the number of Treg cells, e.g., FOXP3+ Treg cells.

152. The composition for use of any one of claims 1 to 75 and 149 to 151, or the composition of any one of claims 76 to 151, wherein the immune response comprises an increase of Type 1 Regulatory (Tr1) cells.

153. The composition for use of any one of claims 1 to 75 and 149 to 152, or the composition of any one of claims 76 to 152, wherein the immune response comprises a decrease of a pro- inflammatory cytokine, wherein the pro-inflammatory cytokine comprises Interferon-γ,Interleukin-1, Interleukin-2, Interleukin-12, Interleukin-16, Interleukin-17, Interleukin-18, Interleukin-21, Interleukin-22, Interleukin-23, Tumor Necrosis Factor-α, or any combination thereof.

154. The composition for use of any one of claims 1 to 75 and 149 to 153, or the composition of any one of claims 76 to 153, wherein the immune response comprises an increase of an immunosupressive cytokine, wherein the immunosuppressive cytokine comprises Interleukin-1R α, Interleukin-4, Interleukin-10, Interleukin-11, Interleukin-13, Tumor Growth Factor-β, Interleukin-33, Interleukin-35, Interleukin-37, or any combination thereof.

155. The composition for use of any one of claims 1 to 75 and 149 to 154, or the composition of any one of claims 75 to 153, wherein at least one MHC-presentable peptide is derived from a protein comprising Chromogranin-A (CHGA), Carboxypeptidase A1(CPA1), C1orf127 protein (C1orf127), Early growth response protein 4 (EGR4), Glutamate decarboxylase 2 (GAD2), Vitamin D-binding protein (GC), Guanine nucleotide-binding protein G(s) subunit alpha isoform XLas (GNAS), Glucose-6-phosphatase 2 (G6PC2 (IGRP)), Insulin (INS), Potassium channel subfamily K member 16 (KCNK16), Kinesin-like protein KIF1A (KIF1A), Neuroendocrine convertase 2 (PCSK2), Pancreas / duodenum homeobox protein 1 (PDX1), Proton-coupled zinc antiporter SLC30A8 (SLC30A8), or any combination thereof.

156. The composition for use of any one of claims 1 to 75 and 149 to 155, or the composition of any one of claims 76 to 155, wherein the nucleotide sequence comprises an RNA, DNA, or any combination thereof.

157. The composition for use of any one of claims 1 to 75 and 149 to 156, or the composition of any one of claims 76 to 156, wherein the nucleotide sequence comprises an mRNA.

158. The composition for use of any one of claims 1 to 75 and 149 to 157, or the composition of any one of claims 76 to 157, wherein one or more of the MHC-presentable peptides are an MHC class II peptide.

159. The composition for use of any one of claims 1 to 75 and 149 to 158, or the composition of any one of claims 76 to 158, wherein all of the MHC-presentable peptides are MHC class II peptides.

160. The composition for use of any one of claims 1 to 75 and 149 to 158, or the composition of any one of claims 76 to 158, wherein one or more of the MHC-presentable peptides are an MHC class I peptide.

161. The composition for use of any one of claims 1 to 75, 149 to 158 and 160, or the composition of any one of claims 76 to 158 and 160, wherein two or more MHC-presentable peptides are a combination of an MHC class I peptide and an MHC class II peptide.

162. The composition for use of any one of claims 1 to 75 and 149 to 161, or the composition of any one of claims 76 to 161, wherein the nucleotide sequence comprises a single open reading frame that encodes one or more MHC-presentable peptides.

163. The composition for use or the composition of claim 162, wherein the single open reading frame encodes all MHC-presentable peptides in the amino acid sequence.

164. The composition for use of any one of claims 1 to 75 and 149 to 161, or the composition of any one of claims 76 to 162, wherein the nucleotide sequence comprises one or more open reading frames that encode one or more MHC-presentable peptides.

165. The composition for use of any one of claims 1 to 75 and 149 to 161, or the composition of any one of claims 76 to 161, wherein the nucleotide sequence comprises a plurality of open reading frames that encodes one or more MHC-presentable peptides.

166. The composition for use of any one of claims 1 to 75 and 149 to 165, or the composition of any one of claims 76 to 165, wherein the amino acid sequence encoded by the nucleotide sequence further comprises MHC-presentable peptides directly linked to each other without a linker.

167. The composition for use of any one of claims 1 to 75 and 149 to 165, or the composition of any one of claims 76 to 165, wherein the amino acid sequence comprising the MHC-presentable peptides further comprises a linker between two MHC-presentable peptides.

168. The composition for use or composition of claim 167, wherein the linker comprises a single amino acid, two amino acids, three amino acids, four amino acids, five amino acids, six amino acids, seven amino acids, eight amino acids, nine amino acids, or ten amino acids.

169. The composition for use or composition of claim 167 or 168, wherein the linker comprises a flexible linker.

170. The composition for use or composition of claim 167 or 168, wherein the linker comprises a cleavable linker.

171. The composition for use or composition of any one of claims 167 to 170, wherein the linker comprises an amino acid sequence selected from the group consisting of the linkers set forth in Table 4.

172. The composition for use of any one of claims 1 to 75 and 149 to 171, or the composition of any one of claims 76 to 171, wherein two or more of the MHC-presentable peptides comprise amino acid sequences of different lengths.

173. The composition for use of any one of claims 1 to 75 and 149 to 172, or the composition of any one of claims 76 to 172, wherein one or more of the MHC-presentable peptides comprises a flank region at the N terminus (N terminus flank) and / or the C terminus (C terminus flank) of the MHC-presentable peptides.

174. The composition for use of any one of claims 1 to 75 and 149 to 173, or the composition of any one of claims 76 to 173, wherein the total length of the amino acid sequence comprises 50- 100 amino acids, 100-200 amino acids, 200-300 amino acids, 300-400 amino acids, 400-500 amino acids, 500-600 amino acids, 600-700 amino acids, 700-800 amino acids, 800-900 amino acids, 900-1000 amino acids, 1000-1100 amino acids, or 1100-1200 amino acids.

175. The composition for use of any one of claims 1 to 75 and 149 to 174, or the composition of any one of claims 76 to 174, wherein the nucleotide sequence further comprises a 5’ UTR.

176. The composition for use of any one of claims 1 to 75 and 149 to 175, or the composition of any one of claims 76 to 175, wherein the nucleotide sequence further comprises a 3’ UTR.

177. The composition for use of any one of claims 1 to 75 and 149 to 176, or the composition of any one of claims 76 to 176, wherein the nucleotide sequence further comprises a poly-A tail.

178. The composition for use of any one of claims 1 to 75 and 149 to 177, or the composition of any one of claims 76 to 177, wherein the nucleotide sequence further comprises a cap structure.

179. The composition for use or the composition of claim 178, wherein the cap structure comprises a 5' cap structure, a 5' cap-0 structure, a 5' cap-l structure, or a 5' cap-2 structure.

180. The composition for use of any one of claims 1 to 75 and 149 to 179, or the composition of any one of claims 75 to 178, wherein the nucleotide sequence comprises a nucleic acid having at least one chemical modification.

181. The composition for use or the composition of claim 180, wherein the chemical modification is in the nucleic acid base, in the nucleic acid sugar, or in the nucleic acid backbone.

182. The composition for use or the composition of claim 180 or 181, wherein the chemical modification in the base comprises pseudouridine, Nl-methylpseudouridine, Nl- ethylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-l-methyl-l-deaza- pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio- dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio- pseudouridine, 4-methoxy-pseudouridine, 4-thio-l -methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methyluridine, 5-methoxyuridine, or 2'- 0-methyl uridine.

183. The composition for use or the composition of claim 180 or 181, wherein the chemical modification in the sugar comprises Locked Nucleic Acid (LNA); 2'-O-alkyl-RNA; 2'-amino- DNA; 2'-fluoro-DNA; arabino nucleic acid (ANA); 2'-fluoro-ANA, hexitol nucleic acid (HNA), intercalating nucleic acid (INA), constrained ethyl nucleic acid (cEt), 2'-O-methyl nucleic acid (2'- OMe), or 2'-O-methoxyethyl nucleic acid (2'-MOE).

184. The composition for use or the composition of any one of claims 180 or 181, wherein the chemical modifications in the backbone comprises a phosphorodiamidate morpholino oligomer (PMO) and / or phosphorothioate (PS) modification.

185. The composition for use of any one of claims 1 to 75 and 149 to 184, or the composition of any one of claims 75 to 183, wherein the MHC-presentable peptides are encoded by a nucleotide sequence.

186. The composition for use of any one of claims 1 to 75 and 149 to 185, or the composition of any one of claims 76 to 185, wherein all the MHC-presentable peptides are encoded by a single nucleotide sequence.

187. The composition for use of any one of claims 1 to 75 and 149 to 185, or the composition of any one of claims 76 to 185, wherein all the MHC-presentable peptides are encoded by at least two heterologous nucleotide sequences.

188. The composition for use of any one of claims 1 to 75 and 149 to 187, or the composition of any one of claims 76 to 187, wherein all of the MHC-presentable peptides are derived from one or more Type 1 Diabetes (T1D) antigens.

189. The composition for use of any one of claims 1 to 75 and 149 to 188, or the composition of any one of claims 76 to 188, wherein one or more of the MHC-presentable peptides are derived from an antigen specific to a subject having Type 1 Diabetes (“subject specific T1D antigen”).

190. The composition for use of any one of claims 1 to 75 and 149 to 189, or the composition of any one of claims 76 to 189, wherein one or more of the MHC-presentable peptides are immunogenic.

191. The composition for use of any one of claims 1 to 75 and 149 to 190, or the composition of any one of claims 76 to 190, wherein the nucleotide sequence or the amino acid sequence is delivered by a delivery agent.

192. The composition for use of any one of claims 1 to 75 and 149 to 191, or the composition of any one of claims 76 to 191, wherein the delivery agent is capable of delivering the nucleotide sequence or the amino acid sequence to a target cell.

193. The composition for use of any one of claims 1 to 75 and 149 to 192, or the composition of any one of claims 76 to 192, wherein the delivery agent comprises a liposome, a lipid nanoparticle, an exosome, a lipid-like particle, a lipoplex, a microvesicle, a vector, or any combination thereof.

194. The composition for use or composition of claim 193, wherein the delivery agent comprises a nanoparticle.

195. The composition for use of any one of claims 192 to 194, or the composition of any one of claims 192 to 194, wherein the target cell is a pancreatic cell, a dendritic cell, a macrophage, a B cell, or a non-professional antigen presenting cell 196. The composition for use of any one of claims 192 to 195, or the composition of any one of claims 192 to 195, wherein the target cell is a tolerogenic cell.

197. The composition for use or the composition of claim 196, wherein the tolerogenic cell is a cell in the liver, optionally selected from a liver sinusoidal endothelial cell, a MARCO+ Kupffer cell, and a monocyte-derived macrophage.

198. The composition for use or the composition of claim 196, wherein the tolerogenic cell is a cell in the spleen, optionally selected from a marginal zone macrophage, a metallophilic macrophage, and a marginal zone dendritic cell.

199. The composition for use of any one of claims 192 to 196, or the composition of any one of claims 192 to 196, wherein the target cell is a pancreatic cell.

200. The composition for use of any one of claims 191 to 199, or the composition of any one of claims 191 to 199, wherein the delivery agent has a negative zeta potential.

201. The composition for use of any one of claims 192 to 200, or the composition of any one of claims 192 to 200, wherein the delivery agent comprises a ligand that binds the target cell.

202. An MHC complex comprising an MHC class I or II molecule and an MHC-presentable peptide comprising at least 8 amino acids (or at least 13 amino acids, e.g., 13, 14, or 15 amino acids) of an MHC-presentable peptide sequence as set forth in Table 1A or Table 1B.

203. An MHC complex comprising an MHC class I or II molecule and an MHC-presentable peptide encoded by the nucleotide sequence in the composition of any one of claims 185 to 201.

204. The MHC complex of claim 202 or 203, which comprises an MHC class I molecule only, an MHC class II molecule only, or both an MHC class I molecule and an MHC class II molecule.

205. An antigen presenting cell (APC) comprising the MHC complex of any one of claims 202 to 204.

206. A pharmaceutical composition comprising the composition of any one of claims 185 to 201, the MHC complex of any one of claims 202 to 204, or the antigen presenting cell of claim 205, and a pharmaceutically acceptable excipient.

207. The composition for use of any one of claims 1 to 75 and 149 to 201, further comprising administering an immunomodulator.

208. The composition of any one of claims 76 to 201, the MHC complex of any one of claims 202 to 204, the antigen presenting cell of claim 205, or the pharmaceutical composition of claim 206, wherein the composition further comprises an immunomodulator.

209. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 208, wherein the immunomodulator is encoded by a nucleotide sequence.

210. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 209, wherein the immunomodulator is encoded by the same nucleotide sequence that encodes the MHC-presentable peptides.

211. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of any one of claims 207 to 210, wherein the immunomodulator comprises an immunomodulatory cytokine or a nucleic acid encoding the immunomodulatory cytokine.

212. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 211, wherein the immunomodulatory cytokine comprises IL- 2, IL-10, TGF-β, IL-37, IL-27, IL-35, CXCL11, CCL17, OX40L / Jagged-1, Vasoactive Intestinal MHC-presentable peptide (VIP), or any combination thereof.

213. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 211, wherein the immunomodulatory cytokine comprises an IL-2 protein that preferentially activates the IL-2Rαβγ receptor complex relative to the IL-2Rβγ receptor complex.

214. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 211 or 212, wherein the immunomodulatory cytokine comprises an IL-10 protein.

215. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 211 or 212, wherein the immunomodulatory cytokine comprises a TGF-β protein.

216. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of any one of claims 207 to 215, wherein the immunomodulator comprises or further comprises a nucleic acid encoding an intracellular or transmembrane immunomodulatory protein.

217. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 216, wherein the intracellular or transmembrane immunomodulatory protein comprises PD-L1, PD-L2, ICOS ligand, ILT3, ILT4, BTLA, Fas, CD39, indoleamine 2,3-dioxygenase 1 (IDO1), CHUK, Ikkb, GILZ, or any combination thereof.

218. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 207 or 208, wherein the immunomodulator comprises an immunomodulatory compound.

219. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of claim 218, wherein the immunomodulatory compound comprises vitamin A, vitamin D, adenosine, kynurenine, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), fingolimod (FTY720), interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, or any combination thereof.

220. The composition for use, composition, MHC complex, antigen presenting cell, or pharmaceutical composition of any one of claims 207 to 219, wherein the immunomodulator is in or on the delivery agent.

221. A kit comprising the composition for use of any one of claims 1 to 75, 149 to 201, 207, and 209 to 220, the composition of any one of claims 76 to 201, and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220, and instructions for use.

222. A method of increasing CD4+ Treg cells in a subject in need thereof comprising administering the composition of any one of claims 76 to 201 and 208 to 220 or the pharmaceutical composition of any one of claims 206 and 208 to 220 to the subject.

223. A method of decreasing CD8+ Treg cells in a subject in need thereof comprising administering the composition of any one of claims 76 to 201 and 208 to 220 or the pharmaceutical composition of any one of claims 206 and 208 to 220 to the subject.

224. A method of increasing Type 1 Regulatory (Tr1) cells or inducing T-regulatory 35 (iTr35) cells in a subject in need thereof comprising administering the composition of any one of claims 76 to 201 and 208 to 220 or the pharmaceutical composition of any one of claims 206 and 208 to 220 to the subject.

225. A method of increasing LAG3+CD49b+ Tr1 cells in a subject in need thereof comprising administering the composition of any one of claims 76 to 201 and 208 to 220 or the pharmaceutical composition of any one of claims 206 and 208 to 220 to the subject.

226. A method of inducing an anergy of T effector cells in a subject in need thereof comprising administering the composition of any one of claims 76 to 201 and 208 to 220 or the pharmaceutical composition of any one of claims 206 and 208 to 220 to the subject.

227. A method of inducing an anergy of CD4+ T effector cells in a subject in need thereof comprising administering the composition of any one of claims 76 to 201 and 208 to 220 or the pharmaceutical composition of any one of claims 206 and 208 to 220 to the subject.

228. A method of producing the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220, comprising adding a nucleotide sequence encoding the MHC-presentable peptide in the nucleotide sequence.

229. A method of inducing a tolerizing immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220.

230. A method of inducing a T cell response against Type 1 Diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220.

231. A method of preventing or treating Type 1 Diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220.

232. Use of the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220 in the manufacture of a medicament for inducing a tolerizing immune response against Type 1 Diabetes.

233. Use of the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220 for use in the manufacture of a medicament for treating or preventing Type 1 Diabetes.

234. The composition for use of any one of claims 1 to 75, 149 to 201, 207, and 209 to 220, the composition of any one of claims 76 to 201 and 208 to 220, the MHC complex of any one of claims 202 to 204 and 208 to 220, the antigen presenting cell of any one of claims 205 and 208 to 220, or the pharmaceutical composition of any one of claims 206 and 208 to 220, the method of any one of claims 222 to 231, or the use of claim 232 or 233, wherein the composition, the MHC complex, the antigen presenting cell, the pharmaceutical composition, or the medicament is administered intravenously, subcutaneously, intramuscularly, intra-arterially, intra-articularly, intracardiacly, intradermally, intraperitoneally, intrathecally, or transdermally.

235. Means for inducing a tolerogenic immune response in a subject in need thereof, in combination with a pharmaceutically acceptable carrier.

236. A method of treating or preventing type I diabetes in a subject in need thereof comprising administering to the subject a means for inducing a tolerogenic immune response in combination with a pharmaceutically acceptable carrier.

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