Methods and compositions for modulating stem-like t cells in autoimmune disease

Abstract

Provided herein are methods for treating an autoimmune disease or a fibrotic disease in a subject comprising administering to the subject an effective amount of an agent to modulate the activity of a population of T-cells expressing one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject.

Description

[0001]Atty. Dkt. No.: 116639-3110 METHODS AND COMPOSITIONS FOR MODULATING STEM-LIKE T CELLS IN AUTOIMMUNE DISEASE CROSS-REFERENCE TO RELATED PATENT APPLICATION This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 661,859, filed June 19, 2024, the contents of which are incorporated herein by reference in their entireties. FIELD OF THE DISCLOSURE The present disclosure generally relates to the treatment of autoimmune diseases or fibrotic diseases by modulating the expression and / or activity of Stem-like T cells, including but not limited to via the modulation of the targets identified herein. BACKGROUND OF THE DISCLOSURE The following description of the background of the present technology is provided simply as an aid in understanding the present technology and is not admitted describing or being prior art to the present technology. Ulcerative colitis (UC), along with Crohn’s Disease (CD), is one of the two major forms of inflammatory bowel disease (IBD). UC is typified by more continuous lesions that are confined to the colon, and which are not as deep in the tissue as those in CD. UC is a debilitating inflammatory disease characterized by T cell-driven inflammation. The initiating immune stimuli likely are microbial antigens, but UC is classified as an autoimmune disease because of the resulting, immune-mediated tissue damage. Although currently approved biological and small molecule therapies have shown clinical benefit, nearly 50% of UC patients fail to respond to treatment. Importantly, treatment failures over time and disease relapses are common, raising the possibility that current treatments may fail to target sufficiently the pathogenic immune cell populations or their effector molecules that orchestrate disease pathogenesis. -1- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Provided herein, inter alia, are solutions to these and other problems in the art. SUMMARY OF THE DISCLOSURE To address the above-identified limitations in the art, this disclosure provides methods for the treatment and methods for diagnosing an autoimmune disease or a fibrotic disease in a subject. Embodiments according to the present disclosure will be described more fully hereinafter. Aspects of the disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Applicant has discovered strong associations between the abundance of certain colonic T cell subsets and autoimmune or fibrotic diseases (e.g., UC disease). For example, Applicant has found support from mouse models of colitis that implicate homologous T cell types in disease pathogenesis. The putative pathogenic T cell subsets include IL-17 cytokine producing CD4+T cells (TH17) and CD8+T cells (TC17), follicular helper CD4+T cells (TFH), IL-26 producing CD8+T cells, Granzyme K- and EOMES-expressing CD8+T cells. Recent studies in mouse autoimmune disease models reveal the existence of pool of stem-like autoimmune progenitor CD4+and CD8+T cells expressing the transcription factor T cell factor 1 (TCF1, encoded by TCF7). These cells play a critical role in driving pathogenesis by sustaining the generation of pathogenic effector T cells in the context of persistent antigenic stimulation, with stem-like CD4+T cells in mice also important for allograft rejection. Stem-like CD8+T cells were initially characterized in mouse models of chronic viral infections and cancer, where they are the precursor population for both exhausted and effector T cells. They display distinguishing features both from naïve and conventional memory T cells, such as expression of surface proteins also expressed by TFH cells, including the co-inhibitory receptor PD-112,19, which renders them highly responsive to anti-PD1 therapies in these models. Whether similar stem-like T cells play a role in the pathogenesis of human autoimmune disease remains uncertain. In an -2- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 unbiased approach to analyze T cells in patients with UC, Applicant focused on data indicating the presence of stem-like T cells within colonic tissue, and assessed their relationship with other potentially pathogenic T cell subsets in the colon. Additionally, Applicant analyzed if these cell types are important for pathogenesis in a mouse colitis model. An aspect of the disclosure is directed to a method of treating an autoimmune disease or a fibrotic disease in a subject, the method comprising, or alternatively consisting essentially of, or yet further consisting of administering to the subject an effective amount of an agent to modulate the activity of a population of T-cells expressing one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject. In some embodiments, the method involves administering to the subject an effective amount of an agent that modulates expression in T cells of one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject. In some embodiments, the T-cells are CD4+ or CD8+ T-cells. In some embodiments, the agent is selected from a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. In some embodiments, the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding one or more of the targets identified herein. In some embodiments, administration of the agent induces higher or lower than baseline expression of the one or more of the targets in T-cells. In some embodiments, higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression. In some embodiments, baseline expression comprises normalized mean gene expression. -3- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In some embodiments, the method further includes administering to the subject an additional therapy for the autoimmune disease or the fibrotic disease. In some embodiments, the additional therapy comprises, or alternatively consists essentially of, or yet further consists of one or more monoclonal antibodies for the treatment of the autoimmune or the fibrotic disease. Another aspect of the disclosure is directed to a method of diagnosing an autoimmune disease or fibrotic disease in a subject, the method comprising, or alternatively consisting essentially of, or yet further consisting of contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels is a diagnostic indicator of the autoimmune or the fibrotic disease, or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not a diagnostic indicator of the autoimmune disease or fibrotic disease. In some embodiments, the absence of the one or more genes is at the baseline expression levels. Another aspect of the disclosure is directed to a method of identifying a subject that will or is likely to respond to one or more of an autoimmune therapy or a fibrotic disease therapy, the method comprising, or alternatively consisting essentially of, or yet further consisting of contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the autoimmune therapy or the fibrotic disease therapy. In some embodiments, baseline expression is normalized mean gene expression for the assayed genes. In some embodiments, higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression -4- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 relative to baseline expression. In some embodiments, higher than baseline expression of the one or more genes is at least about a 0.5-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 0.5-fold decrease in expression relative to baseline expression. In some embodiments, the method further includes administering to a patient in need thereof an autoimmune therapy or a fibrotic disease therapy. In some embodiments, the autoimmune therapy or the fibrotic disease therapy is one or more of hormonal therapy, immunotherapy, or monoclonal antibody therapy. In some embodiments, the sample is contacted with an agent, optionally including a detectable label or tag. In some embodiments, the detectable label or tag comprises, or alternatively consists essentially of, or yet further consists of a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. In some embodiments, the agent comprises, or alternatively consists essentially of, or yet further consists of a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene. In some embodiments, the polypeptide comprises, or alternatively consists essentially of, or yet further consists of an antibody, an antigen binding fragment thereof, or a receptor that binds to the gene. In some embodiments, the antibody is an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. In some embodiments, the IgG is an IgG1, IgG2, IgG3 or IgG4. In some embodiments, the antigen binding fragment is a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. -5- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In some embodiments, the agent is contacted with the sample in conditions under which it can bind to the one or more targets. In some embodiments, the method comprises, or alternatively consists essentially of, or yet further consists of detection of the antibody-protein product by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. In some embodiments, the sample comprises, or alternatively consists essentially of, or yet further consists of cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. In some embodiments, the autoimmune disease or fibrotic disease comprises, or alternatively consists essentially of, or yet further consists of polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatica, Spondyloarthritides, pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity, gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, drug-resistant rheumatoid arthritis, neuromyelitis optica, Kawasaki disease, juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease, Castleman’s disease, asthma, allergic asthma, allergic encephalomyelitis, arthritis, reactive arthritis, psoriatic arthritis, enteropathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity, allergies, systemic lupus erythematosus, cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s syndrome, inflammatory muscle disorders, Wegener's -6- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, diabetes mellitus, autoimmune hematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia, autoimmune uveitis, keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis, idiopathic nephrotic syndrome, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dyslipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, autoimmune polyglandular syndrome, immune infertility and immune-mediated infertility. In some embodiments, the autoimmune disease or fibrotic disease comprises ulcerative colitis, Crohn's disease, or rheumatoid arthritis. In some embodiments, the one or more targets are selected from: TIAM1, IGFBP4, IL21, IL21-R, PASK, TMEM155, HMOX1, CD81, CAV1, FCRL3, PGM2L1, and ICA1. -7- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 BRIEF DESCRIPTION OF THE FIGURES FIG. 1A shows an overview of a study where single-cell transcriptomes of sorted T cells were isolated from endoscopically inflamed and non-inflamed colonic tissue samples of patients from both sexes with active ulcerative colitis (UC) that were naïve to biological treatment modes. FIG. 1B shows single-cell transcriptomes of colonic T cells from healthy controls and UC patients displayed by uniform manifold approximation and projection (UMAP). Seurat- based clustering of 13,887 T cells, colored based on cluster type, and labels indicate assigned T cell subset cluster identity. FIG. 1C shows a gene set enrichment analysis (GSEA) plot shows enrichment of the indicated gene signatures obtained from the sources shown. False discovery rate (FDR) and normalized enrichment score (NES) were determined using fgsea package on R. FIG. 1D shows a plot with Z-score average expression (color scale) and percentage of cells (size scale) that expressed selected marker gene transcripts that were significantly enriched (FDR ≤ 0.05) in the indicated cluster when compared to the other colonic CD8+T cells. FIG. 1E shows a similar plot as FIG. 1D but for CD4+T cells. FIG. 1F is a re-analysis of single-cell transcriptomes of T cells isolated from intestinal tissue of healthy controls, UC and CD patients (Left and middle plot). Single-cell data was integrated with Applicant datasets to obtain similar clustering patterns and cell subset labels. Plots on the right top, show T cells isolated from colon and ileum of CD patients; right bottom show T cells isolated from CD patients pre- and post-treatment with TNF blockers. FIG. 1G is a re-analysis of T cells isolated from intestinal tissue of healthy controls, UC and CD patients. Single-cell data was integrated with Applicant datasets to obtain similar clustering patterns and cell subset labels. -8- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 1H is a plot showing Z-score average expression and % of cells expressing selected genes that are significantly enriched (FDR ≤ 0.05) in the indicated cluster from the three studies, highlighting shared TSCfeatures in UC and CD. FIG. 2A shows the percentages of the indicated CD8+T cell subsets in the four indicated sources of colonic tissue, including healthy controls (n = 5), patients in remission (n = 7), non- inflamed tissue from those with active disease (n = 10), and inflamed tissue (n = 14). Data from paired non-inflamed and inflamed colonic tissue samples of patients with active UC (n = 10) are shown in the bottom plots. The bar graphs depict mean± SEM, each symbol represents data from an individual subject. Statistical significance for the comparisons was computed using Kruskal–Wallis test and adjustments were made for multiple comparisons (top) and Student’s paired two-tailed t test (bottom); *P < 0.05, **P < 0.01, ***P < 0.001 and ns, non-significant P value. FIG. 2B shows a plot with Seurat-normalized mean expression (color scale) and percentage of cells (size scale) that expressed selected transcripts significantly enriched (FDR ≤ 0.05) in stem-like CD8+T cell when compared to the remainder of the colonic CD8+T cells. FIG. 2C is a UMAP showing Seurat-normalized expression levels of the indicated transcripts in single CD8+T cells. FIG. 2D shows transcripts were significantly enriched in the main groups of colonic CD8+T cells from the four tissue sources. FIG. 2E is a single-cell TCR sequence analysis of CD8+T cells isolated from inflamed colonic tissue of patients with active UC. The bars show the number of cells with shared TCRs, subsets with shared TCRs indicated by the vertical lines. FIG. 2F is a UMAP showing stem-like CD8+T cells that shared TCR sequences with TC17 and TGZMK cells. -9- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 3A shows the percentage of the indicated CD4+T cell subsets from the indicated sources of colonic tissue obtained from healthy controls (n = 5), patients with UC in remission (n = 7), with active disease from non-inflamed tissue (n = 10) and inflamed tissue (n = 14); Data from paired inflamed and non-inflamed colonic tissue samples from patients with active UC is shown in the bottom plots (n = 10). Bar graphs depict mean± SEM, each symbol represents data from an individual subject. Statistical significance for the comparisons was computed using Kruskal–Wallis test and adjustments were made for multiple comparisons (top), and Student’s paired two-tailed t test (bottom); *P < 0.05, **P < 0.01, ***P < 0.001 and ns, non-significant P value FIG. 3B shows single-cell trajectory analysis showing relationship between cells in different CD4+T cells clusters (line), constructed using Monocle 3 and visualized by UMAP. FIG. 3C shows a plot with Z-score average expression (color scale) and percentage of cells (size scale) that expressed selected transcripts that are significantly enriched (FDR ≤ 0.05) in stem-like CD4+T cells and TH17 cells. FIG. 3D is a UMAP showing Seurat-normalized expression of indicated gene transcripts in single colonic CD4+T cells. FIG. 3E is a heatmap showing expression of the significantly enriched transcripts (adjusted P value < 0.05) in the indicated clusters. FIG. 3F shows single-cell TCR sequence analysis of CD4+T cells isolated from inflamed colonic tissue of patients with active UC. The bars show the number of cells with shared TCRs, the subsets with shared TCRs indicated by the vertical lines. FIG. 3G is a UMAP showing stem-like CD4+T cells that shared TCR sequences with TINTand TH17 cells clusters. -10- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 3H is a plot showing the correlation between the proportion of stem-like CD4+and CD8+T cells present in inflamed colonic tissues of patients with active UC (n = 14). Significance for the correlation was computed using Spearman correlation. FIG. 3I shows CD4, CD8, TCF1, and Hoechst immunofluorescence staining of colonic tissues. TCF1 detects proliferating epithelial cells as well as some T cells. Nuclear TCF1 staining in T cells is surrounded by a rim of CD4 or CD8 staining, as indicated by arrows for representative cells. FIG. 3J shows TCF1+CD4+and TCF1+CD8+T cell counts from the indicated groups (n = 7 for healthy; n = 11 for inflamed tissue from patients with active UC). FIG. 4A is an illustration of the adoptive T cell transfer model of colitis. FIG. 4B shows the body weight measurements of recipient Rag1- / -mice; the graph depicts mean ± SEM (n = 6 for each genotype). Data are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using two-way ANOVA. FIG. 4C (left) shows histology scores for the degree of colon tissue inflammation (n = 6 for each genotype); two samples with filled dots were shown in the representative images. FIG. 4C (right) shows hematoxylin and eosin (H&E) staining of mouse colon tissues from Rag1- / -mice that received the indicated CD4+T cells. Scale bars indicated. Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; statistical significance for the comparisons was computed using student’s unpaired two-tailed t test. FIG. 4D shows CD4+T cell numbers from colon LP of the indicated recipient Rag1- / -mice (Bcl6fl / fln = 4; Bcl6fl / flCd4Cren = 5). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; data are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. -11- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 4E shows representative flow cytometry contour plots and frequency of colon LP CD4+T cells that expressed the indicated cytokines following ex vivo stimulation with Phorbol 12-myristate 13-acetate plus ionomycin for 4 hours (left), and unstimulated CD4+T cells that expressed surface CD8α (right) (Bcl6fl / fln = 4; Bcl6fl / flCd4Cren = 5). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; data are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 5A shows single-cell transcriptomes of colon LP CD4+T cells from recipient Rag1- / -mice displayed by UMAP. Seurat-based clustering of 18,860 cells combined from WT and Bcl6fl / flCd4Cremice, colored based on cluster type. FIG. 5B is an RNA velocity analysis visualized by UMAP depicting likely developmental trajectories of WT (top) and BCL-6 deficient (lower) CD4+T cells. Arrows indicate velocity streamlines. FIG. 5C shows UMAPs showing Seurat-normalized expression levels of Il17a and Il22 gene transcripts in single colonic CD4+T cells. FIG. 5D is a GSEA plot shows enrichment of TFHand TH17 gene signatures in cluster 4 compared to the rest of the colonic CD4+T cells; P value and normalized enrichment score (NES) determined using fgsea package on R. FIG. 5E shows UMAPs showing colonic CD4+T cells from each Rag1- / -mice that received BCL-6-deficient or WT CD4+T cells. FIG. 5E (right) is a plot showing the percentage of CD4-CTL (cluster 2) and TH17 (cluster 4) cells in the indicated recipient Rag1- / -mice (Bcl6fl / fln = 6; Bcl6fl / flCd4Cren = 6). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. -12- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 6A is an illustration of the adoptive T cell transfer model of colitis with 2.5 x 105splenic CD4+CD45RBhighCD25–T cells from Tcf7fl / flCd4Cremice or Tcf7fl / flmice transferred into Rag1- / -mice. FIG. 6B shows CD4+T cell numbers from colon LP of the indicated recipient Rag1- / -mice (Tcf7fl / fln = 7; Tcf7fl / flCd4Cren = 6). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; data are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 6C shows body weight measurements of recipient Rag1- / -mice; the graph depicts mean ± SEM (Tcf7fl / fln = 7; Tcf7fl / flCd4Cren = 6). Data are representative from one of at least two independent experiments with similar results. Statistical significance for the comparisons was computed using two-way ANOVA. FIG. 6D (left) shows histology scores for the degree of colon tissue inflammation (combination of 2 independent experiments; Tcf7fl / fln = 13; Tcf7fl / flCd4Cren = 12); two samples with filled green dots were shown as representative images on the right. FIG. 6D (right) shows hematoxylin and eosin (H&E) staining of mouse colon tissues from Rag1- / -mice that received the indicated CD4+T cells. Scale bars indicated. Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 7A is an illustration of the secondary adoptive T cell transfer model of colitis with 2.5 x 105splenic CD4+CD45RBhighCD25–T cells from Tcf7GFPreporter mice transferred into Rag1- / -mice. 8 weeks later, GFP+or GFPnegCD4+T cells from the LP lymphocytes (LPL) or spleen and mesenteric lymph nodes (MLNs), labeled as secondary lymphoid organs (SLO), were transferred into separate cohorts of disease-free Rag1- / -mice. FIG. 7B shows representative flow cytometry contour plots show frequency of GFP- expressing CD4+T cells in recipient Rag1- / -mice following the primary transfer. -13- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 7C shows body weight measurements of the recipient Rag1- / -mice in the secondary transfer model; the graph depicts mean ± SEM. Statistical significance for the comparisons was computed using two-way ANOVA. FIG. 7D shows histology scores for the degree of colon tissue inflammation (n = 7 or 8 for each group). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; data are from one experiment. Statistical significance for the comparisons was computed Kruskal–Wallis test and adjustments were made for multiple comparisons. FIG. 7E shows representative flow cytometry contour plots of colon LPL from the recipient Rag1- / -mice in the secondary transfer model. FIG. 7F shows CD4+T cell numbers from colon LP of the indicated recipient Rag1- / -mice in the secondary transfer (n = 7 or 8 for each group). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; data are from one experiment. Statistical significance for the comparisons was computed using Kruskal–Wallis test and adjustments were made for multiple comparisons. FIG. 8A is an illustration of the adoptive T cell transfer model of colitis with 1 x 105splenic naïve CD4+CD45RBhighCD25–T cells and / or 5 x 105splenic TCRβ+CD8β+CD4- T cells transferred into Rag1- / -mice. FIG. 8B shows body weight measurements of recipient Rag1- / -mice. The plot depicts mean ± SEM. Statistical significance for the comparisons was computed using two-way ANOVA. FIG. 8C shows representative flow cytometry contour plots and numbers of colon LP CD4+and CD8+T cells (CD4+T cell transfer and CD4+ +CD8+T cell transfer, n = 5; CD8+T cell transfer n = 6). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; all data from are representative of one of two independent experiments. -14- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 8D shows an illustration of the adoptive T cell transfer model of colitis with splenic wildtype naïve CD4+CD45RBhighCD25– T cells and splenic TCRβ+CD8β+CD4– T cells from Bcl6fl / flCd8aCremice or Bcl6fl / flmice. FIG. 8E shows CD8+T cell numbers from colon LP of the indicated recipient Rag1- / -mice (Bcl6fl / fln = 5; Bcl6fl / flCd8aCren = 6). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; all data from are representative of one of two independent experiments. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 8F (Top) shows single-cell transcriptomes of colon LP CD8+T cells from recipient Rag1- / -mice displayed by UMAP. Seurat-based clustering of cells from Bcl6fl / fland Bcl6fl / flCd8aCremice, colored based on cluster type. FIG. 8F (Bottom) is a plot showing the percentage of stem-like CD8+T cells in the indicated recipient Rag1- / -mice. Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; all data from are representative of one of two independent experiments. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 8G shows UMAPs showing Seurat-normalized expression levels of indicated gene transcripts or Tcf7+CD8+T cell gene signature in single colonic CD8+T cells. FIG. 8H is a GSEA plot shows enrichment of the indicated gene signatures in the indicated clusters compared to the rest of the colonic CD8+T cells. FIG. 8I is a violin plot shows Seurat-normalized expression levels of Gzmb transcripts in single colonic CD8+T cells. FIG. 8J shows representative flow cytometry plot and mean fluorescence intensity (MFI) of colon LP CD8+T cells that expressed Granzyme B following ex vivo stimulation (Bcl6fl / fln = -15- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 5; Bcl6fl / flCd8aCren = 6). Bar graphs depict mean ± SEM, each symbol represents data from an individual mouse; all data from are representative of one of two independent experiments. Statistical significance for the comparisons was computed using Student’s unpaired two-tailed t test. FIG. 9 shows the presence of TCF7-expressing T cells (TSC) in the colon of a UC patient. Spatial transcriptomic analysis of colon tissue from an UC patient with active disease. Colon section shows spatial location of the major cell types (color code), based on their transcriptional profile – assayed on the Xenium platform;TCF7+ T cells (Tsc) – red dots. FIG. 10 is a plot showing Z-score average expression (color scale) and percentage of cells (size scale) expressing selected transcripts that were enriched in CD4+and / or CD8+TSCcompared to other cells (REST); re-analysis of indicated datasets. FIG. 11A illustrates the adoptive T cell transfer model of colitis. FIG. 11B shows the body weight of recipient Rag1- / -mice; Plot depicts mean ± SEM. FIG. 11C shows T cell numbers from colon LP of the indicated recipient Rag1- / -mice. FIG. 11D (Left) shows histology scores for the degree of colon tissue inflammation; FIG. 11D (Right) shows representative H&E staining of mouse colon tissues from Rag1- / -mice that received wildtype (left) and TCF1-deficient CD4+T cells. FIG. 12 (left) shows TCF1 expression in CD4+T cells from Tcf7f / f, and Tcf7f / fdLckCre+mice and (right) TCF1 expression in CD4+T cells from Tcf7f / fCd4Cre-ERT2and Tcf7f / fCd4Cre+ERT2mice following tamoxifen treatment. FIG. 13A illustrates the adoptive CD8+and CD4+T cells co-transfer model of colitis. FIG. 13B shows the body weight of recipient Rag1- / -mice; Plot depicts mean ± SEM. -16- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 FIG. 13C shows CD8+T cell numbers from colon LP of the indicated recipient Rag1- / -mice. FIG. 13D (Left) shows histology scores for the degree of colon tissue inflammation; FIG. 13D (Right) shows representative H&E staining of mouse colon tissues from Rag1- / -mice for the indicated conditions. FIG. 14 demonstrates the presence of TSCin CD (left) and rheumatoid arthritis (RA, right). Re-analysis of published single-cell datasets from patients with CD (left) and RA (right). UMAP shows Seurat-normalized expression levels of gene signature scores for stem-like CD4+T cells and CD8+T cells, highlighting the presence of TSC-like subsets in CD and RA. DETAILED DESCRIPTION Embodiments according to the present disclosure will be described more fully hereinafter. Aspects of the disclosure may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, particular, non-limiting exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior disclosure. -17- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology and recombinant DNA, which are within the skill of the art. See, e.g., Sambrook and Russell eds, (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., N.Y.); MacPherson et al. (1991) PCR 1: A Practical Approach (IRL Press at Oxford University Press); MacPherson et al. (1995) PCR 2: A Practical Approach; Harlow and Lane eds. (1999) Antibodies, A Laboratory Manual; Freshney (2005) Culture of Animal Cells: A Manual of Basic Technique, 5th edition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Pat. No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds, (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); and Herzenberg et al. eds (1996) Weir's Handbook of Experimental Immunology. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The practice of the present technology will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. Unless the context indicates otherwise, it is specifically intended that the various features of the disclosure described herein can be used in any combination. Moreover, the disclosure also contemplates that in some embodiments, any feature or combination of features set forth herein -18- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 can be excluded or omitted. To illustrate, if the specification states that a complex comprises components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and disclaimed singularly or in any combination. Unless explicitly indicated otherwise, all specified embodiments, features, and terms intend to include both the recited embodiment, feature, or term and biological equivalents thereof. All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied ( + ) or ( - ) by increments of 1.0 or 0.1, as appropriate, or alternatively by a variation of + / - 15 %, or alternatively 10%, or alternatively 5%, or alternatively 2% and such ranges are included. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art. Throughout this disclosure, various publications, patents and published patent specifications may be referenced by an identifying citation or by an Arabic numeral. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure in their entirety to more fully describe the state of the art to which this disclosure pertains. Definitions As used in the description of the disclosure and the appended claims, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. As used herein, the term “comprising” is intended to mean that the compositions and methods include the recited elements, but do not exclude others. As used herein, the transitional phrase consisting essentially of (and grammatical variants) is to be interpreted as encompassing -19- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the recited embodiment. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising”. “Consisting of” shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions disclosed herein. Aspects defined by each of these transition terms are within the scope of the present disclosure. The term “about” as used herein when referring to a measurable value such as an amount or concentration and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. As used herein, the terms “increased”, “decreased”, “high”, “low” or any grammatical variation thereof refer to a variation of about 90%, 80%, 50%, 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the reference composition, polypeptide, protein, etc. The terms or “acceptable,” “effective,” or “sufficient” when used to describe the selection of any components, ranges, dose forms, etc. disclosed herein intend that said component, range, dose form, etc. is suitable for the disclosed purpose. Also as used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”). An equivalent of a polynucleotide (referred to herein as the reference) shares at least 50% (or at least 60%, or at least 70%, or at least 80%, or at least 90%) identity to the reference, and encodes the same polypeptide as the one encoded by the reference, or encodes an equivalent of the polypeptide encoded by the reference. To arrive at a position or a consecutive segment of a test sequence equivalent to (or corresponding to)an / a amino acid / nucleotide residue or a consecutive segment of a reference -20- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 sequence, a sequence alignment is performed between the test and reference sequences. The positions or segments aligned to each other are determined as equivalents. The term “analogue” refers to an equivalent having one or more modified amino acids and one or more amino acids replaced with another amino acid. Such modification may include but is not limited to conjugation with a molecule (for example, a small molecule, a cytotoxic molecule, a linker, a pH-sensitive linker, and / or a thiol linker), sialylation, polysialylation, O- glycosylation, N-glycosylation, myristoylation, palmitoylation, isoprenylation or prenylation, glipyatyon, lipoylation, phosphopantetheinylation, ethanolamine phosphoglycerol attachment, diphthamide formation, hypusine formation, acylation, acetylation, formylation, alkylation, methylation, amidation, citrullination, deamidation, eliminylation, ISGylation, SUMOylation, ubiquitination, neddylation, pupylation, biotinylation, carbamylation, oxidation, pegylation, glycation, carbamylation, carbonylation, spontaneous isopeptide bond formation, butyrylation, gamma-carboxylation, malonylation, hydroxylation, iodination, nucleotide addition, phosphate ester (O-linked) or phosphoramidate (N-linked) formation, phosphorylation, adenylylation, uridylylation, propionylation, pyroglutamate formation, S-glutathionylation, S-nitrosylation, S- sulfenylation, S-sulfinylation, S-sulfonylation, succinylation, and / or sulfation. The term “albumin equivalent,” comprises, or consists essentially of, or yet further consists of, polypeptides which can be expressed at a reasonable quantity and which still retains or improves on certain albumin properties, including the binding of the albumin fragment to an FcRn receptor, as is known in the art or described herein. The term “affinity tag” refers to a polypeptide that may be included within a fusion protein to allow detection of the fusion protein and / or purification of the fusion protein from the cellular milieu using a ligand that is able to bind to, i.e., has affinity for, the affinity tag. The ligand may be, but is not limited to, an antibody, a resin, or a complementary polypeptide. An affinity tag may comprise a small peptide, commonly a peptide of approximately 4 to 16 amino acids in length, or it may comprise a larger polypeptide. Commonly used affinity tags include polyarginine, FLAG, V5, polyhistidine, c-Myc, Strep II, maltose binding protein (MBP), N- utilization substance protein A (NusA), thioredoxin (Trx), and glutathione S-transferase (GST), -21- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 among others (for examples, see GST Gene Fusion System Handbook - Sigma-Aldrich). In an embodiment the affinity tag is a polyhistidine tag, for example a His6 tag. The inclusion of an affinity tag in a fusion protein allows the fusion protein to be purified from the cellular milieu by affinity purification, using an affinity medium that is able to tightly and specifically bind the affinity tag. The affinity medium may comprise, for example, a metal-charged resin or a ligand covalently linked to a stationary phase (matrix) such as agarose or metal beads. For example, polyhistidine tagged fusion proteins (also referred to as His tagged fusion proteins) can be recovered by immobilized metal ion chromatography using Ni2+or Co2+loaded resins, anti- FLAG affinity gels may be used to capture FLAG tagged fusion proteins, and glutathione cross- linked to a solid support such as agarose may be used to capture GST tagged fusion proteins. As used herein the terms “purification”, “purifying”, or “separating” refer to the process of isolating one or more polypeptides from a complex mixture, such as a cell lysate or a mixture of polypeptides. The purification, separation, or isolation need not be complete, i.e., some components of the complex mixture may remain with the one or more polypeptides after the purification process. However, the product of purification should be enriched for the one or more polypeptides relative to the complex mixture before purification and a significant portion of the other components initially present within the complex mixture should be removed by the purification process. The term “cell” as used herein may refer to either a prokaryotic or eukaryotic cell, optionally obtained from a subject or a commercially available source. “Eukaryotic cells” comprise all of the life kingdoms except monera. They can be easily distinguished through a membrane-bound nucleus. Animals, plants, fungi, and protists are eukaryotes or organisms whose cells are organized into complex structures by internal membranes and a cytoskeleton. The most characteristic membrane-bound structure is the nucleus. Unless specifically recited, the term “host” includes a eukaryotic host, including, for example, yeast, higher plant, insect and mammalian cells. Non-limiting examples of eukaryotic -22- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 cells or hosts include simian, bovine, porcine, murine, rat, avian, reptilian and human, e.g., HEK293 cells, Chinese Hamster Ovary (CHO) cells and 293T cells. “Prokaryotic cells” that usually lack a nucleus or any other membrane-bound organelles and are divided into two domains, bacteria and archaea. In addition to chromosomal DNA, these cells can also contain genetic information in a circular loop called an episome. Bacterial cells are very small, roughly the size of an animal mitochondrion (about 1-2 μm in diameter and 10 μm long). Prokaryotic cells feature three major shapes: rod shaped, spherical, and spiral. Instead of going through elaborate replication processes like eukaryotes, bacterial cells divide by binary fission. Examples include but are not limited to Bacillus bacteria, E. coli bacterium, and Salmonella bacterium. The term “encode” as it is applied to nucleic acid sequences refers to a polynucleotide which is said to “encode” a polypeptide if, in its native state or when manipulated by methods well known to those skilled in the art, can be transcribed and / or translated to produce the mRNA for the polypeptide and / or a fragment thereof. The antisense strand is the complement of such a nucleic acid, and the encoding sequence can be deduced therefrom. As used herein, “expression” refers to the process by which polynucleotides are transcribed into mRNA and / or the process by which the transcribed mRNA is subsequently being translated into peptides, polypeptides, or proteins. If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell. In some aspects, baseline expression is assessed via immunohistochemistry or flow- cytometry of tissue biopsies (i.e. healthy adjacent tissue) and comprises, consists of, or consists essentially of normalized mean expression. In some aspects, expression of one or more of the targets disclosed herein will be measured in biopsies and compared to baseline levels, where higher than baseline expression of one or more of the targets disclosed herein comprises, consists of, or consists essentially of at least about a 2 or more, or about 3, or about 4, or about 5, or about 6, or about 7, or about 8, or about 9, or about 10, or about 11, or about 12, or about 13, or about -23- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 14, or about 15 fold increase in expression relative to baseline expression and / or lower than baseline expression of one or more of the targets disclosed herein is at least about a 2 or more, or about 3, or about 4, or about 5, or about 6, or about 7, or about 8, or about 9, or about 10, or about 11, or about 12, or about 13, or about 14, or about 15 fold decrease in expression relative to baseline expression. As used herein, the term “target” refers to a specific molecule (as non-limiting examples, a protein, gene, or receptor) within a cell that is the focus of a biological process or therapeutic intervention. In certain embodiments, the one or more of the targets disclosed herein are selected from those targets and / or genes listed in the accompanying Figures. In some embodiments, the one or more targets are selected from TIAM1, IGFBP4, IL21, IL21-R, PASK, TMEM155, HMOX1, CD81, CAV1, FCRL3, PGM2L1, and ICA1. The TIAM1 gene encodes a RAC1-specific guanine nucleotide exchange factor (GEF). GEFs mediate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). This gene regulates RAC1 signaling pathways that affect cell shape, migration, adhesion, growth, survival, and polarity, as well as influencing actin cytoskeletal formation, endocytosis, and membrane trafficking. This gene thus plays an important role in cell invasion, metastasis, and carcinogenesis. The IGFBP4 gene is a member of the insulin-like growth factor binding protein (IGFBP) family and encodes a protein with an IGFBP domain and a thyroglobulin type-I domain. The protein binds both insulin-like growth factors (IGFs) I and II and circulates in the plasma in both glycosylated and non-glycosylated forms. Binding of this protein prolongs the half-life of the IGFs and alters their interaction with cell surface receptors. The IL21 (interleukin 21) gene encodes a member of the common-gamma chain family of cytokines with immunoregulatory activity. The encoded protein plays a role in both the innate and adaptive immune responses by inducing the differentiation, proliferation and activity of multiple target cells including macrophages, natural killer cells, B cells and cytotoxic T cells. -24- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Dysregulation of this gene plays a role in multiple immune-mediated diseases including lupus, psoriasis and chronic inflammatory diseases. IL21R (Interleukin-21 receptor) is a cytokine receptor that plays a crucial role in the immune system by mediating the effects of IL-21. IL21R transduces the growth promoting signal of IL21, and is important for the proliferation and differentiation of T cells, B cells, and natural killer (NK) cells. The PASK (PAS domain containing serine / threonine kinase) gene encodes a member of the serine / threonine kinase family that contains two PAS domains. Expression of this gene is regulated by glucose, and the encoded protein plays a role in the regulation of insulin gene expression. Downregulation of this gene may play a role in type 2 diabetes. The TMEM155 gene encodes a protein called transmembrane protein 155. This protein plays a crucial role in maintaining cellular homeostasis and regulating immune responses. TMEM155 is primarily expressed in immune cells, such as macrophages, dendritic cells, and neutrophils, and its function is essential for immune surveillance and defense against pathogens. HMOX1 (heme oxygenase 1 gene) is a gene that encodes for the enzyme heme oxygenase 1. Heme oxygenase, an essential enzyme in heme catabolism, cleaves heme to form biliverdin, which is subsequently converted to bilirubin by biliverdin reductase, and carbon monoxide, a putative neurotransmitter. Heme oxygenase activity is induced by its substrate heme and by various nonheme substances. Heme oxygenase occurs as 2 isozymes: an inducible HMOX1 and a constitutive heme oxygenase-2. The CD81 gene encodes CD81 protein, which is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known -25- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 to complex with integrins. This protein appears to promote muscle cell fusion and support myotube maintenance. The CAV1 gene encodes caveolin-1, a protein primarily found in caveolae, which are small invaginations of the cell membrane. Caveolin-1 plays a crucial role in various cellular processes, including signal transduction, lipid metabolism, and cell growth. It acts as a scaffolding protein within caveolae, influencing the activity of other proteins involved in these processes. The FCRL3 gene encodes the FCRL3 (Fc receptor-like 3 or FcRH3) protein which is a member of the immunoglobulin receptor superfamily and is one of several Fc receptor-like glycoproteins clustered on the long arm of chromosome 1. The encoded protein contains immunoreceptor-tyrosine activation motifs and immunoreceptor-tyrosine inhibitory motifs in its cytoplasmic domain and may play a role in regulation of the immune system. Mutations in this gene have been associated with rheumatoid arthritis, autoimmune thyroid disease, and systemic lupus erythematosus. The PGM2L1 gene encodes the phosphoglucomutase 2 like 1 (PGM2L1) protein, which is an enzyme that plays a role in glucose metabolism. Specifically, the protein functions as a glucose 1,6-bisphosphate synthase. Mutations in the PGM2L1 gene are associated with a neurodevelopmental disorder characterized by hypotonia, dysmorphic features, and skin abnormalities. The ICA1 (islet cell autoantigen 1) gene encodes a protein with an arfaptin homology domain that is found both in the cytosol and as membrane-bound form on the Golgi complex and immature secretory granules. This protein is believed to be an autoantigen in insulin-dependent diabetes mellitus and primary Sjogren's syndrome. The activity of any of the targets as described herein may be modulated in the presence of any one of the agents as described herein. The activity may be any process or function performed by the target as described herein. -26- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 The term “isolated” or a grammatical variation thereof as used herein refers to molecules or biologicals or cellular materials being substantially free from other materials. As used herein, the term “functional” may be used to modify any molecule, biological, or cellular material to intend that it accomplishes a particular, specified effect. As used herein, the terms “nucleic acid sequence” and “polynucleotide” are used interchangeably to refer to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides. Thus, this term includes, but is not limited to, single-, double-, or multi- stranded DNA or RNA, genomic DNA, complementary DNA (cDNA), DNA-RNA hybrids, or a polymer comprising purine and pyrimidine bases or other natural, chemically or biochemically modified, non-natural, or derivatized nucleotide bases. In certain embodiments, the polynucleotide comprises and / or encodes a messenger RNA (mRNA), a short hairpin RNA, and / or small hairpin RNA. In one embodiment, the polynucleotide is or encodes an mRNA. In certain embodiments, the polynucleotide is a double-strand (ds) DNA, such as an engineered ds DNA or a ds cDNA synthesized from a single-stranded RNA. The terms “polynucleotide” and “oligonucleotide” are used interchangeably and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides or analogs thereof. Polynucleotides can have any three-dimensional structure and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: a gene or gene fragment (for example, a probe, primer, EST or SAGE tag), exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, RNAi, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide can comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polynucleotide. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, such as by conjugation with a labeling component. The term also refers to both double- and single-stranded molecules. Unless -27- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 otherwise specified or required, any embodiment disclosed herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. A polynucleotide is composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); thymine (T); and uracil (U) for thymine when the polynucleotide is RNA. Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. The term “isolated” or “recombinant” as used herein with respect to nucleic acids, such as DNA or RNA, refers to molecules separated from other DNAs or RNAs, respectively that are present in the natural source of the macromolecule as well as polypeptides. The term “isolated or recombinant nucleic acid” is meant to include nucleic acid fragments which are not naturally occurring as fragments and would not be found in the natural state. The term “isolated” is also used herein to refer to polynucleotides, polypeptides and proteins that are isolated from other cellular proteins and is meant to encompass both purified and recombinant polypeptides. In other embodiments, the term “isolated or recombinant” means separated from constituents, cellular and otherwise, in which the cell, tissue, polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, which are normally associated in nature. For example, an isolated cell is a cell that is separated from tissue or cells of dissimilar phenotype or genotype. An isolated polynucleotide is separated from the 3′ and 5′ contiguous nucleotides with which it is normally associated in its native or natural environment, e.g., on the chromosome. As is apparent to those of skill in the art, a non-naturally occurring polynucleotide, peptide, polypeptide, protein, antibody or fragment(s) thereof, does not require “isolation” to distinguish it from its naturally occurring counterpart. -28- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 As used herein, the terms “engineered” “synthetic” “recombinant” and “non-naturally occurring” are interchangeable and indicate intentional human manipulation, for example, a modification from its naturally occurring form, and / or a sequence optimization. The terms “equivalent” or “biological equivalent” are used interchangeably when referring to a particular molecule, biological, or cellular material and intend those having minimal homology while still maintaining desired structure or functionality (for example, having a similar functional activity). It should be understood, without being explicitly stated that when referring to an equivalent or biological equivalent to a reference polypeptide, protein, or polynucleotide , that an equivalent or biological equivalent has the recited structural relationship to the reference polypeptide, protein, or polynucleotide and equivalent or substantially equivalent biological activity. For example, non-limiting examples of equivalent polypeptides, proteins, or polynucleotides include a polypeptide, protein or polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity thereto or for polypeptide, polynucleotide or protein sequences across the length of the reference polynucleotide. Alternatively, an equivalent polypeptide is one that is encoded by a polynucleotide or its complement that hybridizes under conditions of high stringency to a polynucleotide encoding such reference polypeptide sequences and that have substantially equivalent or equivalent biological activity. Conditions of high stringency are described herein and incorporated herein by reference. Alternatively, an equivalent thereof is a polypeptide encoded by a polynucleotide or a complement thereto, having at least 70%, or alternatively at least 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% identity, or at least 97% sequence identity across the length of the reference polynucleotide to the reference polynucleotide, e.g., the wild-type polynucleotide. Such equivalent polypeptides have the same biological activity as the reference polynucleotide. Non-limiting examples of equivalent polypeptides, include a polynucleotide having at least 60%, or alternatively at least 65%, or alternatively at least 70%, or alternatively at least -29- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 75%, or alternatively 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95%, or alternatively at least 97%, identity to a reference polynucleotide. An equivalent also intends a polynucleotide or its complement that hybridizes under conditions of high stringency to a reference polynucleotide. Such equivalent polypeptides have the same biological activity as the reference polynucleotide. A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) having a certain percentage (for example, 80%, 85%, 90%, or 95%) of “sequence identity” to another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences across the length of the reference polynucleotide. The alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in Current Protocols in Molecular Biology (Ausubel et al., eds. 1987) Supplement 30, section 7.7.18, Table 7.7.1.In certain embodiments, default parameters are used for alignment. A non-limiting exemplary alignment program is BLAST, using default parameters. In particular, exemplary programs include BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi- bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan. 13, 2017). “Homology” or “identity” or “similarity” refers to sequence similarity between two peptides or between two nucleic acid molecules. Homology can be determined by comparing a position in each sequence that may be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same base or amino acid, then the molecules are homologous at that position. A degree of homology between sequences is a function of the number of matching or homologous positions shared by the sequences. An “unrelated” or “non- -30- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 homologous” sequence shares less than 40% identity, or alternatively less than 25% identity, with one of the sequences of the present disclosure as determined using BLAST, using default parameters or BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi- bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan. 13, 2017). As used herein, the term “at least 90% identical” refers to an identity of two compared sequences (polynucleotides or polypeptides) of about 90% to about 100%. It also include an identity of at least at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, about 91% to about 100%, about 92% to about 100%, about 93% to about 100%, about 94% to about 100%, about 95% to about 100%, about 96% to about 100%, about 97% to about 100%, about 98% to about 100%, or about 99% to about 100% as determined using BLAST, using default parameters or BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi-bin / BLAST. Sequence identity and percent identity can be determined by incorporating them into clustalW (available at the web address:genome.jp / tools / clustalw / , last accessed on Jan. 13, 2017). “Homology” or “identity” or “similarity” can also refer to two nucleic acid molecules that hybridize under stringent conditions. -31- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 As used herein, the terms “retain” “similar” and “same” are used interchangeably while describing a function, an activity or an functional activity of a polynucleotide, a protein and / or a peptide, referring to a functional activity of at least about 20% (including but not limited to: at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or about 100%) of the activity of the reference protein, polynucleotide and / or peptide using methods disclosed herein. It is to be inferred without explicit recitation and unless otherwise intended, that when the present disclosure relates to a polypeptide, protein, polynucleotide or antibody, an equivalent or a biologically equivalent of such is intended within the scope of this disclosure. As used herein, the term “biological equivalent thereof” is intended to be synonymous with “equivalent thereof” when referring to a reference protein, antibody, fragment, polypeptide or nucleic acid, intends those having minimal homology while still maintaining desired structure or functionality. Unless specifically recited herein, it is contemplated that any polynucleotide, polypeptide or protein mentioned herein also includes equivalents thereof. In one aspect, an equivalent polynucleotide is one that hybridizes under stringent conditions to the polynucleotide or complement of the polynucleotide as described herein for use in the described methods. In another aspect, an equivalent antibody or antigen binding polypeptide intends one that binds with at least 70%, or alternatively at least 75%, or alternatively at least 80%, or alternatively at least 85%, or alternatively at least 90%, or alternatively at least 95% affinity or higher affinity to a reference antibody or antigen binding fragment. In another aspect, the equivalent thereof competes with the binding of the antibody or antigen binding fragment to its antigen under a competitive ELISA assay. In another aspect, an equivalent intends at least about 80% homology or identity and alternatively, at least about 85%, or alternatively at least about 90%, or alternatively at least about 95%, or alternatively 98% percent homology or identity and exhibits substantially equivalent biological activity to the reference protein, polypeptide or nucleic acid. A polynucleotide or polynucleotide region (or a polypeptide or polypeptide region) having a certain percentage (for example, 80%, 85%, 90%, or 95%) of “sequence identity” to -32- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 another sequence means that, when aligned, that percentage of bases (or amino acids) are the same in comparing the two sequences. The alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in Current Protocols in Molecular Biology (Ausubel et al., eds. 1987) Supplement 30, section 7.7.18, Table 7.7.1. In certain embodiments, default parameters are used for alignment. A non-limiting exemplary alignment program is BLAST, using default parameters. In particular, exemplary programs include BLASTN and BLASTP, using the following default parameters: Genetic code=standard; filter=none; strand=both; cutoff=60; expect=10; Matrix=BLOSUM62; Descriptions=50 sequences; sort by=HIGH SCORE; Databases=non-redundant, GenBank+EMBL+DDBJ+PDB+GenBank CDS translations+SwissProtein+SPupdate+PIR. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi- bin / BLAST. Sequence identity and percent identity were determined by incorporating them into clustalW (available at the web address:align.genome.jp, last accessed on Mar. 7, 2011). As used herein, “oligonucleotide” refers to a molecule that has a sequence of nucleic acid bases on a backbone comprised mainly of identical monomer units at defined intervals. The bases are arranged on the backbone in such a way that they can bind with a nucleic acid having a sequence of bases that are complementary to the bases of the oligonucleotide. The most common oligonucleotides have a backbone of sugar phosphate units. A distinction may be made between oligodeoxyribonucleotides that do not have a hydroxyl group at the 2' position and oligoribonucleotides that have a hydroxyl group at the 2' position. Oligonucleotides may also include derivatives, in which the hydrogen of the hydroxyl group is replaced with organic groups, e.g., an allyl group. One or more bases of the oligonucleotide may also be modified to include a phosphorothioate bond (e.g., one of the two oxygen atoms in the phosphate backbone which is not involved in the internucleotide bridge, is replaced by a sulfur atom) to increase resistance to nuclease degradation. The exact size of the oligonucleotide will depend on many factors, which in turn depend on the ultimate function or use of the oligonucleotide. The oligonucleotide may be generated in any manner, including, for example, chemical synthesis, DNA replication, restriction endonuclease digestion of plasmids or phage DNA, reverse -33- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 transcription, PCR, or a combination thereof. The oligonucleotide may be modified e.g., by addition of a methyl group, a biotin or digoxigenin moiety, a fluorescent tag or by using radioactive nucleotides. “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. “Hybridization” refers to a reaction in which one or more polynucleotides react to form a complex that is stabilized via hydrogen bonding between the bases of the nucleotide residues. The hydrogen bonding may occur by Watson-Crick base pairing, Hoogstein binding, or in any other sequence-specific manner. The complex may comprise two strands forming a duplex structure, three or more strands forming a multi-stranded complex, a single self-hybridizing strand, or any combination of these. A hybridization reaction may constitute a step in a more extensive process, such as the initiation of a PCR reaction, or the enzymatic cleavage of a polynucleotide by a ribozyme. Examples of stringent hybridization conditions include: incubation temperatures of about 25° C. to about 37° C.; hybridization buffer concentrations of about 6×SSC to about 10×SSC; formamide concentrations of about 0% to about 25%; and wash solutions from about 4×SSC to about 8×SSC. Examples of moderate hybridization conditions include: incubation temperatures of about 40° C. to about 50° C.; buffer concentrations of about 9×SSC to about 2×SSC; formamide concentrations of about 30% to about 50%; and wash solutions of about 5×SSC to -34- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 about 2×SSC. Examples of high stringency conditions include: incubation temperatures of about 55° C. to about 68° C.; buffer concentrations of about 1×SSC to about 0.1×SSC; formamide concentrations of about 55% to about 75%; and wash solutions of about 1×SSC, 0.1×SSC, or deionized water. In general, hybridization incubation times are from 5 minutes to 24 hours, with 1, 2, or more washing steps, and wash incubation times are about 1, 2, or 15 minutes. SSC is 0.15 M NaCl and 15 mM citrate buffer. It is understood that equivalents of SSC using other buffer systems can be employed. The term “protein”, “peptide” and “polypeptide” are used interchangeably and in their broadest sense to refer to a compound of two or more subunits of amino acids, amino acid analogs or peptidomimetics. The subunits may be linked by peptide bonds. In another aspect, the subunit may be linked by other bonds, e.g., ester, ether, etc. A protein or peptide must contain at least two amino acids and no limitation is placed on the maximum number of amino acids which may comprise a protein’s or peptide’s sequence. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D and L optical isomers, amino acid analogs and peptidomimetics. As used herein, a consecutive amino acid sequence refers to a sequence having at least two amino acids. However, it is noted that a consecutive amino acid sequence of a first part and a second part does not limit the amino acid sequence to have the first part directly conjugated to the second part. It is also possible that the first part is linked to the second part via a third part, such as a link, thus forming one consecutive amino acid sequence. A polynucleotide disclosed herein can be delivered to a cell or tissue using a gene delivery vehicle. “Gene delivery,” “gene transfer” “mRNA-based delivery”, “transducing,” and the like as used herein, are terms referring to the introduction of an exogenous polynucleotide (sometimes referred to as a “transgene”) into a host cell, irrespective of the method used for the introduction. Such methods include a variety of well-known techniques such as vector-mediated gene transfer (by, e.g., viral infection / transfection, or various other protein-based or lipid-based gene delivery complexes, including for example protamine complexes, lipid nanoparticles, -35- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 polymeric nanoparticles, lipid-polymer hybrid nanoparticles, and inorganic nanoparticles, or combinations thereof) as well as techniques facilitating the delivery of “naked” polynucleotides (such as electroporation, “gene gun” delivery and various other techniques used for the introduction of polynucleotides). The introduced polynucleotide can be unmodified or can comprise one or more modifications; for example, a modified mRNA may comprise ARCA capping; enzymatic polyadenylation to add a tail of 100-250 adenosine residues; and substitution of one or both of cytidine with 5-methylcytidine and / or uridine with pseudouridine. The introduced polynucleotide may be stably or transiently maintained in the host cell. Stable maintenance typically requires that the introduced polynucleotide either contains an origin of replication compatible with the host cell or integrates into a replicon of the host cell such as an extrachromosomal replicon (e.g., a plasmid) or a nuclear or mitochondrial chromosome. A number of vectors are known to be capable of mediating transfer of genes to mammalian cells, as is known in the art and described herein. A “plasmid” is an extra-chromosomal DNA molecule separate from the chromosomal DNA which is capable of replicating independently of the chromosomal DNA. In many cases, it is circular and double-stranded. Plasmids provide a mechanism for horizontal gene transfer within a population of microbes and typically provide a selective advantage under a given environmental state. Plasmids may carry genes that provide resistance to naturally occurring antibiotics in a competitive environmental niche, or alternatively the proteins produced may act as toxins under similar circumstances. “Plasmids” used in genetic engineering are called “plasmid vectors”. Many plasmids are commercially available for such uses. The gene to be replicated is inserted into copies of a plasmid containing genes that make cells resistant to particular antibiotics and a multiple cloning site (MCS, or polylinker), which is a short region containing several commonly used restriction sites allowing the easy insertion of DNA fragments at this location. Another major use of plasmids is to make large amounts of proteins. In this case, researchers grow bacteria containing a plasmid harboring the gene of interest. Just as the bacterium produces proteins to confer its -36- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 antibiotic resistance, it can also be induced to produce large amounts of proteins from the inserted gene. A “yeast artificial chromosome” or “YAC” refers to a vector used to clone large DNA fragments (larger than 100 kb and up to 3000 kb).It is an artificially constructed chromosome and contains the telomeric, centromeric, and replication origin sequences needed for replication and preservation in yeast cells. Built using an initial circular plasmid, they are linearized by using restriction enzymes, and then DNA ligase can add a sequence or gene of interest within the linear molecule by the use of cohesive ends. Yeast expression vectors, such as YACs, YIps (yeast integrating plasmid), and YEps (yeast episomal plasmid), are extremely useful as one can get eukaryotic protein products with posttranslational modifications as yeasts are themselves eukaryotic cells, however YACs have been found to be more unstable than BACs, producing chimeric effects. A “viral vector” is defined as a recombinantly produced virus or viral particle that comprises a polynucleotide to be delivered into a host cell, either in vivo, ex vivo or in vitro. Examples of viral vectors include retroviral vectors, adenovirus vectors, adeno-associated virus vectors, herpes simplex virus vectors, alphavirus vectors and the like. As used herein, the term “animal” refers to living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term “mammal” includes both human and non-human mammals. In one aspect, a “subject” or “patient” to whom the therapies such as for example a combination of modulating one or more of the targets disclosed herein therapy and immune checkpoint inhibitor is administered is preferably a mammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey or human). The subject or patient can be a human, such as an adult patient or a pediatric patient. -37- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 An “effective amount” or “efficacious amount” refers to the amount of an agent, or combined amounts of two or more agents, that, when administered for the treatment of a mammal or other subject, is sufficient to effect such treatment for the disease. The “effective amount” will vary depending on the agent(s), the disease and its severity and the age, weight, etc., of the subject to be treated. As used herein, a biological sample, or a sample, can be obtained from a subject, cell line or cultured cell or tissue. Exemplary samples include, but are not limited to, cell sample, tissue sample, biopsy, liquid samples such as blood and other liquid samples of biological origin (including, but not limited to, ocular fluids (aqueous and vitreous humor), peripheral blood, sera, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper’s fluid or pre-ejaculatory fluid, female ejaculate, sweat, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, ascites, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions / flushing, synovial fluid, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, or umbilical cord blood. In some instances, the sample is a diseased tissue biopsy. In certain embodiments, the terms “disease” “disorder” and “condition” are used interchangeably herein, referring to an autoimmune disorder or fibrotic disorder, a status of being diagnosed with an autoimmune disorder or fibrotic disorder, or a status of being suspect of having an autoimmune disorder or fibrotic disorder. As used herein, the term “extracellular matrix” (ECM) is a three-dimensional network of extracellular macromolecules, such as collagen, enzymes, and glycoproteins, that provide structural and biochemical support to surrounding cells. As used herein, the term “detectable marker” refers to at least one marker capable of directly or indirectly, producing a detectable signal. A non-exhaustive list of this marker includes enzymes which produce a detectable signal, for example by colorimetry, fluorescence, -38- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 luminescence, such as horseradish peroxidase, alkaline phosphatase, β-galactosidase, glucose-6 phosphate, dehydrogenase, chromophores such as fluorescent, luminescent dyes, groups with electron density detected by electron microscopy or by their electrical property such as conductivity, amperometry, voltammetry, impedance, detectable groups, for example whose molecules are of sufficient size to induce detectable modifications in their physical and / or chemical properties, such detection may be accomplished by optical methods such as diffraction, surface plasmon resonance, surface variation, the contact angle change or physical methods such as atomic force spectroscopy, tunnel effect, or radioactive molecules such as32P,35S ,89Zr or125I. As used herein, the term “purification marker” refers to at least one marker useful for purification or identification. A non-exhaustive list of this marker includes His, lacZ, GST, maltose-binding protein, NusA, BCCP, c-myc, CaM, FLAG, GFP, YFP, cherry, thioredoxin, poly(NANP), V5, Snap, HA, chitin-binding protein, Softag 1, Softag 3, Strep, or S-protein. Suitable direct or indirect fluorescence marker comprise FLAG, GFP, YFP, RFP, dTomato, cherry, Cy3, Cy 5, Cy 5.5, Cy 7, DNP, AMCA, Biotin, Digoxigenin, Tamra, Texas Red, rhodamine, Alexa fluors, FITC, TRITC or any other fluorescent dye or hapten. As used herein, “immunophenotyping” refers to the analysis of heterogeneous populations of cells for the purpose of identifying the presence and proportions of the various populations in the sample. Antibodies are used to identify cells by detecting specific antigens (termed markers) expressed by these cells. In an aspect, the cell samples are characterized by immunophenotyping using techniques such as flow cytometry. In alternative aspects, characterizations of the various cell types, (such as T cells, B cells and their subsets) present in a cell sample may be carried out using any suitable methodology such as reverse transcriptase polymerase chain reaction (RT-PCR) or immunocytochemistry (IHC). The phrase “first line” or “second line” or “third line” or “fourth line” or “fifth line” refers to the order of treatment received by a patient. First line therapy regimens are treatments -39- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 given first, whereas second or third line therapy are given after the first line therapy or after the second line therapy, respectively. As used herein, the term “T cell,” refers to a type of lymphocyte that matures in the thymus. T cells play an important role in cell-mediated immunity and are distinguished from other lymphocytes, such as B cells, by the presence of a T-cell receptor on the cell surface. T- cells may either be isolated or obtained from a commercially available source. “T cell” includes all types of immune cells expressing CD3 including T-helper cells (CD4+ cells), cytotoxic T- cells (CD8+ cells), natural killer T-cells, T-regulatory cells (Treg), Tissue-resident memory T cells (TRMcells), stem T cells and gamma-delta T cells. A “cytotoxic cell” includes CD8+ T cells, natural-killer (NK) cells, and neutrophils, which cells are capable of mediating cytotoxicity responses. Non-limiting examples of commercially available T-cell lines include lines BCL2 (AAA) Jurkat (ATCC® CRL-2902™), BCL2 (S70A) Jurkat (ATCC® CRL-2900™), BCL2 (S87A) Jurkat (ATCC® CRL-2901™), BCL2 Jurkat (ATCC® CRL-2899™), Neo Jurkat (ATCC® CRL-2898™), TALL-104 cytotoxic human T cell line (ATCC # CRL-11386). Further examples include but are not limited to mature T-cell lines, e.g., such as Deglis, EBT-8, HPB- MLp-W, HUT 78, HUT 102, Karpas 384, Ki 225, My-La, Se-Ax, SKW-3, SMZ-1 and T34; and immature T- cell lines, e.g., ALL-SIL, Be13, CCRF-CEM, CML-T1, DND-41, DU.528, EU-9, HD-Mar, HPB-ALL, H-SB2, HT-1, JK-T1, Jurkat, Karpas 45, KE-37, KOPT-K1, K-T1, L- KAW, Loucy, MAT, MOLT-1, MOLT 3, MOLT-4, MOLT 13, MOLT-16, MT-1, MT-ALL, P12 / Ichikawa, Peer, PER0117, PER-255, PF-382, PFI-285, RPMI-8402, ST-4, SUP-T1 to T14, TALL-1, TALL-101, TALL-103 / 2, TALL-104, TALL-105, TALL-106, TALL-107, TALL-197, TK-6, TLBR-1, -2, -3, and -4, CCRF-HSB-2 (CCL-120.1), J.RT3-T3.5 (ATCC TIB-153), J45.01 (ATCC CRL-1990), J.CaM1.6 (ATCC CRL-2063), RS4;11 (ATCC CRL-1873), CCRF-CEM (ATCC CRM-CCL-119); and cutaneous T-cell lymphoma lines, e.g., HuT78 (ATCC CRM-TIB- 161), MJ[G11] (ATCC CRL-8294), HuT102 (ATCC TIB-162). Null leukemia cell lines, including but not limited to REH, NALL-1, KM-3, L92-221, are a another commercially available source of immune cells, as are cell lines derived from other leukemias and lymphomas, such as K562 erythroleukemia, THP-1 monocytic leukemia, U937 lymphoma, HEL -40- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 erythroleukemia, HL60 leukemia, HMC-1 leukemia, KG-1 leukemia, U266 myeloma. Non- limiting exemplary sources for such commercially available cell lines include the American Type Culture Collection, or ATCC, (atcc.org / ) and the German Collection of Microorganisms and Cell Cultures (dsmz.de / ). Tissue resident memory cell” or “TRM” cells refer to a subset of long-lived memory T cells that occupy epithelial and mucosal tissues. A “cytotoxic cell” intends a cell that is capable of killing other cells or microbes. Examples of cytotoxic cells include but are not limited to CD8+ T-cells, certain CD4+ T-cells, double-negative T-cells, gamma delta T-cells, natural-killer (NK) cells, NK T-cells, and neutrophils, which cells are capable of mediating cytotoxicity responses. As used herein, the term “CD4+ cytotoxic T-cells” refers to a population of T-cells that express CD4 on their surface and, generally, are ThPOK- (downregulated). These CD4+ cytotoxic T-cells can also be characterized by CD8αα expression, downregulation of Gata3, and upregulation of Runx3 and Tbet. Sequences for the mentioned transcription factors and surface proteins are provided at the following accession numbers: ThPOK (Uniprot: O15156 (human); Q64321 (mouse); also known as ZBTB7B), Gata3 (Uniprot: P23771 (human); P23772 (mouse); P23825 (chicken)), Runx3 (Uniprot: Q13761 (human); Q64131 (mouse); Q91ZK1 (rat)); Tbet (Uniprot: Q9UL17 (human); Q5PSB0 (mouse); E1UGZ0 (rainbow trout), also known as TBX21), CD4 (Uniprot: P01730 (human); P06332 (mouse); P33705 (dog)), and CD8α (Uniprot: P01732 (human); P01731 (mouse); P33706 (dog), CD8αα being a homodimer of this protein). It should be understood that these sequences are non-limiting and that detection of any of these transcription factors and / or surface proteins may employ or target suitable isoforms, fragments, and biological equivalents thereof; further homologous and / or orthologous sequences for relevant species can be found through the Uniprot database, uniprot.org. The term “CD4+ T-cells” refers to T-cells that express CD4 on their surface and, generally, are ThPOK+ (upregulated); these cells include naïve CD4+ T-cells, Th1 T-cells, Th17 -41- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 T-cells, and T-regulatory cells. It is well understood that surface markers, e.g., CD8αα and CD4, can be identified by antibodies to the listed surface markers, i.e., an anti- CD8α antibody or an anti-CD4 antibody. When used in this context the prefix “anti-” and the descriptor “antibody” refer to an antibody, fragment, derivative, or biological equivalent thereof that recognizes or binds the recited protein, e.g., anti-CD4 antibody recognizes and binds CD4. As used herein, the term “CD8+ cytotoxic T-cell” refers to a cytotoxic T-cell and / or a precursor thereof which is CD8+ and expresses CD8αα on its surface. The CD8αα surface expression is an indicator that these CD8+ cytotoxic T-cells have high affinity to the antigen against which they were generated. As used herein, “CD8αα” refers to a homodimer of CD8α (also known as CD8a) that may be expressed on the surface of certain T-cells. Non-limiting exemplary amino acid sequences for CD8α can be found in the Uniprot database under accession numbers P01732 (human CD8α); P01731 (mouse CD8α); P33706 (dog CD8α); other homologs of the same may also be found in the Uniprot database, i.e., at uniprot.org. “CD8αβ” refers to a heterodimer of CD8α and CD8β (also known as CD8b) that is expressed on the surface of CD8+T-cells. Non- limiting exemplary amino acid sequences for CD8β can be found in the Uniprot database under accession numbers P10966 (human CD8β); P10300 (mouse CD8β); P79336 (cat CD8β); other homologs of the same may also be found in the Uniprot database, i.e., at uniprot.org. As used herein, “anti- CD8α” and “anti- CD8β” refer to antibodies or fragments, derivatives, or biological equivalents thereof that recognizes and bind to CD8α and CD8β, respectively. These may be recombinantly expressed, generated by exposing antibody producing cells to CD8α or CD8β, or other means known in the art, using for example, the proteins described herein. Further they can be purchased from commercial vendors, such as but not limited to Becton Dickinson. “Frequency” of cells expressing any one particular molecule, biomarker, or antigen refers to the likelihood of or ratio of cells expressing the molecule, biomarker, or antigen compared to a population of T cells at large. -42- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In general, antagonistic antibodies and / or agents have the ability to bind and deactivate the target receptor in a way that mimics the activity of the ligand. The agent may include a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. An antagonistic antibody intends an antibody, antigen binding fragment, derivative or other modification as described herein that recognizes and binds one or more of the targets disclosed herein. The antagonizing antibodies or agents described in the application may bind to one or more of the targets disclosed herein to decrease, eliminate, and / or otherwise modulate the activity of the one or more of the targets disclosed herein receptor and / or target-expressing cell. Such activities may include proliferation or inhibition of cell signaling activities of the cell upon which the receptor for one or more of the targets disclosed herein is expressed. An agonistic antibody intends an antibody, antigen binding fragment, derivative or other modification as described herein that recognizes and binds one or more of the targets disclosed herein. The agonistic antibodies or agents described in the application may bind to one or more of the targets disclosed herein to increase, expand, and / or otherwise modulate the activity of the one or more of the targets disclosed herein receptor and / or target-expressing cell. Such activities may include proliferation or inhibition of cell signaling activities of the cell upon which the receptor for one or more of the targets disclosed herein is expressed. As used herein, the terms “antibody,” “antibodies” and “immunoglobulin” includes whole antibodies and any antigen binding fragment or a single chain thereof. Thus the term “antibody” includes any protein or peptide containing molecule that comprises at least a portion of an immunoglobulin molecule. The terms “antibody,” “antibodies” and “immunoglobulin” also include immunoglobulins of any isotype, fragments of antibodies which retain specific binding to antigen, including, but not limited to, Fab, Fab′, F(ab)2, Fv, scFv, dsFv, Fd fragments, dAb, VH, VL, VhH, and V-NAR domains; minibodies, diabodies, triabodies, tetrabodies and kappa bodies; multispecific antibody fragments formed from antibody fragments and one or more isolated. Examples of such include, but are not limited to a complementarity determining region -43- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 (CDR) of a heavy or light chain or a ligand binding portion thereof, a heavy chain or light chain variable region, a heavy chain or light chain constant region, a framework (FR) region, or any portion thereof, at least one portion of a binding protein, chimeric antibodies, humanized antibodies, single-chain antibodies, and fusion proteins comprising an antigen-binding portion of an antibody and a non-antibody protein. The variable regions of the heavy and light chains of the immunoglobulin molecule contain a binding domain that interacts with an antigen. The constant regions of the antibodies (Abs) may mediate the binding of the immunoglobulin to host tissues. The term “anti-” when used before a protein name refers to a monoclonal or polyclonal antibody that binds and / or has an affinity to a particular protein. The antibodies can be polyclonal, monoclonal, multispecific (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity. Antibodies can be isolated from any suitable biological source, e.g., murine, rat, sheep and canine. The term “antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. In some embodiments, the term “antibody fragment” refers to at least one portion of an intact antibody, or recombinant variants thereof, and refers to the antigen binding domain, e.g., an antigenic determining variable region of an intact antibody, that is sufficient to confer recognition and specific binding of the antibody fragment to a target, such as an antigen. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, Fv fragments, scFv antibody fragments, linear antibodies, single domain antibodies such as sdAb (either VLor VH), camelid VHH domains, and multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3)(see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide minibodies). “Fab” means a monovalent antigen- -44- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 binding fragment of an immunoglobulin that is composed of the light chain and part of the heavy chain. F(ab′)2 means a bivalent antigen-binding fragment of an immunoglobulin that contains both light chains and part of both heavy chains. As used herein, the term “Fv fragment” or “variable domain fragment” refers to a VH domain and a VL domain of an antibody specifically binding to an antigen, both domains forming together a Fv fragment. In some embodiment, Fv fragments means an antibody fragment comprising the VHand VLdomains of an antibody, wherein these domains are present in a single polypeptide chain as disclosed in Table 4 herein. Generally, the Fv fragment polypeptide further comprises a polypeptide linker between the VHand VLdomains polypeptide that enables the scFv to form. The term “scFv” refers to a fusion protein comprising at least one antibody fragment comprising a variable region of a light chain and at least one antibody fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VLand VHvariable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL. As used herein, the term “antibody heavy chain” refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. As used herein, the term “antibody light chain” refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. Kappa (κ) and lambda (λ) light chains refer to the two major antibody light chain isotypes. As used herein, the term “synthetic antibody” means an antibody, which is generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody, which has been -45- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. As used herein, the term “antibody variant” includes synthetic and engineered forms of antibodies which are altered such that they are not naturally occurring, e.g., antibodies that comprise at least two heavy chain portions but not two complete heavy chains (such as, domain deleted antibodies or minibodies); multi-specific forms of antibodies (e.g., bi-specific, tri- specific, etc.) altered to bind to two or more different antigens or to different epitopes on a single antigen); heavy chain molecules joined to scFv molecules and the like. In addition, the term “antibody variant” includes multivalent forms of antibodies (e.g., trivalent, tetravalent, etc., antibodies that bind to three, four or more copies of the same antigen. As used herein, the term “antigen” or “Ag” is defined as a molecule that provokes an immune response. This immune response may involve either antibody production, or the activation of specific immunologically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA. A skilled artisan will understand that any DNA, which comprises a nucleotide sequence or a partial nucleotide sequence encoding a protein that elicits an immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full-length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit a desired immune response. Moreover, the skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. -46- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 The term “bispecific antibody” refers to an antibody that can simultaneously bind to two different receptors, epitopes or antigens. The bispecific antibodies of the instant disclosure may target and bind antigens on the same cells or different cells. In some aspects, the bispecific antibodies bind to one or more of the targets disclosed herein and a second molecule on the T cell. One or more of the targets disclosed herein may be expressed on a T cell. In some aspects, the second molecule is expressed on the same T cell. In one aspect, the bispecific antibodies of the claimed disclosure increase target specificity for one or more of the targets disclosed herein expressed in T cells, while limiting undesirable off-target activity. In some aspects, the bispecific binds and modulates the expression or activity of one or more of the targets disclosed herein in or on the T cell or the one or more of the targets disclosed herein when expressed on T cells. As used herein, “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous antibody population. Monoclonal antibodies are highly specific, as each monoclonal antibody is directed against a single determinant on the antigen. The antibodies may be detectably labeled, e.g., with a radioisotope, an enzyme which generates a detectable product, a fluorescent protein, and the like. The antibodies may be further conjugated to other moieties, such as members of specific binding pairs, e.g., biotin (member of biotin-avidin specific binding pair), and the like. The antibodies may also be bound to a solid support, including, but not limited to, polystyrene plates or beads, and the like. Monoclonal antibodies may be generated using hybridoma techniques or recombinant DNA methods known in the art. A hybridoma is a cell that is produced in the laboratory from the fusion of an antibody-producing lymphocyte and a non-antibody producing cancer cell, usually a myeloma or lymphoma. A hybridoma proliferates and produces a continuous sample of a specific monoclonal antibody. Alternative techniques for generating or selecting antibodies include in vitro exposure of lymphocytes to antigens of interest, and screening of antibody display libraries in cells, phage, or similar systems. The term “human antibody” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The -47- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term “human antibody” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. Thus, as used herein, the term “human antibody” refers to an antibody in which substantially every part of the protein (e.g., CDR, framework, CL, CHdomains (e.g., CH1, CH2, CH3), hinge, (VL, VH)) is substantially non-immunogenic in humans, with only minor sequence changes or variations. Similarly, antibodies designated primate (monkey, baboon, chimpanzee, etc.), rodent (mouse, rat, rabbit, guinea pig, hamster, and the like) and other mammals designate such species, sub-genus, genus, sub-family, family specific antibodies. Further, chimeric antibodies include any combination of the above. Such changes or variations optionally retain or reduce the immunogenicity in humans or other species relative to non- modified antibodies. Thus, a human antibody is distinct from a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and / or light chain) genes. Further, when a human antibody is a single chain antibody, it can comprise a linker peptide that is not found in native human antibodies. For example, an Fv can comprise a linker peptide, such as two to about eight glycine or other amino acid residues, which connects the variable region of the heavy chain and the variable region of the light chain. Such linker peptides are considered to be of human origin. As used herein, a human antibody is “derived from” a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, e.g., by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library. A human antibody that is “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germline immunoglobulins. A selected human antibody typically is at least 90% identical in amino acids sequence to an amino acid -48- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as being human when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a human antibody may be at least 95%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence will display no more than 10 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene. In certain cases, the human antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene. A “human monoclonal antibody” refers to antibodies displaying a single binding specificity which have variable and constant regions derived from human germline immunoglobulin sequences. The term also intends recombinant human antibodies. Methods to making these antibodies are described herein. In one embodiment, an antibody as used herein may be a recombinant antibody. The term “recombinant human antibody”, as used herein, includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and -49- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo. Methods to making these antibodies are described herein. As used herein, chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, typically by genetic engineering, from antibody variable and constant region genes belonging to different species. As used herein, the term “humanized antibody” or “humanized immunoglobulin” refers to a human / non-human chimeric antibody that contains a minimal sequence derived from non- human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a variable region of the recipient are replaced by residues from a variable region of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity and capacity. Humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. The humanized antibody can optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin, a non-human antibody containing one or more amino acids in a framework region, a constant region or a CDR, that have been substituted with a correspondingly positioned amino acid from a human antibody. In general, humanized antibodies are expected to produce a reduced immune response in a human host, as compared to a non-humanized version of the same antibody. The humanized antibodies may have conservative amino acid substitutions which have substantially no effect on antigen binding or other antibody functions. Conservative substitutions groupings include: glycine-alanine, valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine- valine, serine-threonine and asparagine-glutamine. The antibodies of the present disclosure may bind to an antigen or molecule. The terms “polyclonal antibody” or “polyclonal antibody composition” as used herein refer to a preparation of antibodies that are derived from different B-cell lines. They are a mixture of immunoglobulin molecules secreted against a specific antigen, each recognizing a different epitope. -50- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 As used herein, the term “antibody derivative”, comprises a full-length antibody or a fragment of an antibody, wherein one or more of the amino acids are chemically modified by alkylation, pegylation, acylation, ester formation or amide formation or the like, e.g., for linking the antibody to a second molecule. This includes, but is not limited to, pegylated antibodies, cysteine-pegylated antibodies, and variants thereof. Complementarity determining regions (CDRs) are part of the variable region of an antibody or a T cell receptor generated by B-cell s and T-cells respectively, wherein these molecules bind to their specific antigen (also called epitope). In certain embodiments, the terms “variable region” and “variable domain” are used interchangeably, referring to the polypeptide of a light or heavy chain of an antibody that varies greatly in its sequence of amino acid residues from one antibody to another, and that determines the conformation of the combining site which confers the specificity of the antibody for a particular antigen. In a further embodiment, the variable region is about 90 amino acids long to about 200 amino acids long, including but not limited to about 100 amino acids long, or alternatively about 110 amino acids long, or alternatively about 120 amino acids long, or alternatively about 130 amino acids long, or alternatively about 140 amino acids long, or alternatively about 150 amino acids long, or alternatively about 160 amino acids long, or alternatively about 170 amino acids long, or alternatively about 180 amino acids long, or alternatively about 190 amino acids long. In certain embodiments, a variable region of an amino acid sequence, as used herein, refers to that the first about 100 amino acids, or alternatively about 110 amino acids, or alternatively about 120 amino acids, or alternatively about 130 amino acids, or alternatively about 140 amino acids, or alternatively about 150 amino acids of the amino acid sequence (including or excluding a signal peptide if applicable) is the variable region. A set of CDRs constitutes a paratope also called an antigen-binding site, which is a part of an antibody that recognizes and binds to an antigen. There are three CDRs (CDR1, CDR2 and CDR3), arranged non-consecutively, optionally from the amino terminus to the carboxyl terminus, on the amino acid sequence of a variable region of an antigen receptor, such as a heavy chain or a light chain. As used herein, CDRn refers to a CDRn in an immunoglobulin chain or -51- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 derived from an immunoglobulin chain, wherein the number n is selected from 1-3. In one embodiment, CDRLn refers to a CDRn in a light chain or derived from a light chain, wherein the number n is selected from 1-3; while CDRHn refers to a CDRn in a heavy chain or derived from a heavy chain, wherein the number n is selected from 1-3. In certain embodiments, framework region (FR) refers to the part of a variable region which is not a CDR. In certain embodiments, FRn refers to a FR in a heavy chain or a light chain or derived from a heavy chain or a light chain, and wherein the number n is selected from 1-4. In certain embodiments, a variable region comprises or consists essentially of, or yet further consists of the following (optionally following the order as provided, and further optionally from the amino terminus to the carboxyl terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Variable regions and / or CDRs of an antibody or a fragment thereof can be determined by one of skill in the art, for example, using publicly or commercially available tools. Non-limiting examples of such tools include, IgBlast (accessible at ncbi.nlm.nih.gov / igblast / ), Scaligner (available from drugdesigntech at scaligner.com / ), IMGT rules and / or tools (see, for example, imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html, also accessible at imgt.org / ), Chothia Canonical Assignment (accessible at bioinf.org.uk / abs / chothia.html), Antigen receptor Numbering And Receptor ClassificatIon (ANARCI, accessible at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), the Kabat numbering method / scheme (e.g., Kabat, E.A., et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242,) or the Paratome web server (accessible at ofranlab.org / paratome / , see Vered Kunik, et al, Nucleic Acids Research, Volume 40, Issue W1, 1 July 2012, Pages W521–W524). “Immune response” broadly refers to the antigen-specific responses of lymphocytes to foreign substances. The terms “immunogen” and “immunogenic” refer to molecules with the capacity to elicit an immune response. All immunogens are antigens, however, not all antigens are immunogenic. An immune response disclosed herein can be humoral (via antibody activity) or cell-mediated (via T cell activation). The response may occur in vivo or in vitro. The skilled artisan will understand that a variety of macromolecules, including proteins, nucleic acids, fatty -52- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 acids, lipids, lipopolysaccharides and polysaccharides have the potential to be immunogenic. The skilled artisan will further understand that nucleic acids encoding a molecule capable of eliciting an immune response necessarily encode an immunogen. The artisan will further understand that immunogens are not limited to full-length molecules, but may include partial molecules. As used herein, the term “inducing an immune response in a subject” or “modulating an immune response” are terms well understood in the art and intends that an increase or decrease of at least about 0.5-fold, about 2-fold, at least about 5-fold, at least about 10-fold, at least about 100-fold, at least about 500-fold, or at least about 1000-fold or more in an immune response (i.e. T cell or antibody response) to an antigen (or epitope) and can be detected or measured by various methods known in the art. For example, the frequency or activity of antigen-specific T cells can be measured by multiple methods, including, but not limited to, flow cytometry, RNA- sequencing or in vitro assays. As used herein, the term “modulating activity” refers to increasing or decreasing the activity of specific T cell populations associated with an immune response. Modulating of activity may be accomplished by the administration of agents, including antibodies, that target and bind to specific T cell receptors in order to activate the T cell population expressing that molecule. Modulation may occur when the T cells are engaged by costimulatory ligands, agonistic or antagonistic antibodies, or cytokines. In some aspects, modulating activity may include the administration of an agent that targets a molecule on a T cell. In some aspects, the molecule is one or more of the targets disclosed herein and the agent is an antibody that targets one or more of the targets disclosed herein, thus activating or inhibiting a T cell expressing the one or more of the targets disclosed herein. An “immunotherapy agent” means a type of treatment which modulates a patient’s own immune system to treat an autoimmune disorder or fibrotic disorder, including but not limited to a physical intervene, a chemical substance, a biological molecule or particle, a cell, a tissue or organ, or any combinations thereof, modulating a patient's immune response against an autoimmune disorder or fibrotic disorder. Non-limiting examples of immunotherapy agents -53- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 include antibodies, immune regulators, checkpoint inhibitors, an antisense oligonucleotide (ASO), a RNA interference (RNAi), a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) system, a viral vector, and a CAR therapy. Antisense oligonucleotides (ASOs) are oligonucleotides capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20–24 (normally 21) base pairs in length, similar to miRNA, and operating within the RNA interference (RNAi) pathway. It interferes with the expression of specific genes with complementary nucleotide sequences by degrading mRNA after transcription, preventing translation. As used herein, immune checkpoint refers to a regulator and / or modulator of the immune system). Their interaction activates either inhibitory or activating immune signaling pathways. Thus, a checkpoint may contain one of the two signals: an stimulatory immune checkpoint that stimulates an immune response, and an inhibitory immune checkpoint inhibiting an immune response. In some embodiments, the immune checkpoint is crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. As used herein, the term “recombinant host cell,” “recombinant cell,” “engineered host cell,” or “engineered cell,” means a cell into which a recombinant expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” or “cell” as used herein. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in total DNA complement) to the -54- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 original parent cell due to natural, accidental, or deliberate mutation and / or change. A host cell includes a cell transfected or infected in vivo or in vitro with a recombinant vector, an expression vector, or a nucleic acid encoding an antibody of the present disclosure. A host cell, which comprises a recombinant vector, expression vector, or a nucleic acid encoding an antibody disclosed herein, may also be referred to as a “recombinant host cell,” “engineered host cell,” or “engineered cell”. As used herein, the term “host cell” refers to a cell, which may be used in a process for purifying an immunogenic protein or recombinant antibody in accordance with the present disclosure. Such host cell expresses the protein of interest (the antibody disclosed herein). A host cell may also be referred to as a protein-expressing cell. “Host cell” refers not only to the particular subject cell but to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein. A host cell, according to the present disclosure, may be, but is not limited to, prokaryotic cells, eukaryotic cells, archeobacteria, bacterial cells, insect cells, yeast, mammal cells, and / or plant cells. Bacteria envisioned as host cells can be either gram-negative or gram-positive, e.g., Escherichia coli, Erwinia sp., Klebsellia sp., Lactobacillus sp. or Bacillus subtilis. In some embodiments, the host cell is a yeast cell. In that embodiment, the yeast host cell is selected from the group consisting of Saccharomyces cerevisiae, Hansenula polymorpha, and Pichia pastoris. A “composition” is intended to mean a combination of active agent and another compound or composition, inert (for example, a detectable agent or label) or active, such as an adjuvant , diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers. Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri, tetra-oligosaccharides, and oligosaccharides; derivatized -55- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1- 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components, which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol. A “pharmaceutical composition” is intended to include the combination of an active polypeptide, polynucleotide or antibody with a carrier, inert or active such as a solid support, making the composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. “Pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions disclosed herein. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They may be selected with respect to the -56- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. “Administration” can be effected in one dose, continuously or intermittently throughout the course of treatment. Methods of determining the most effective means and dosage of administration are known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents are known in the art. Route of administration can also be determined and method of determining the most effective route of administration are known to those of skill in the art and will vary with the composition used for treatment, the purpose of the treatment, the health condition or disease stage of the subject being treated, and target cell or tissue. Non-limiting examples of route of administration include oral administration, nasal administration, injection, and topical application. An agent of the present disclosure can be administered for therapy by any suitable route of administration. It will also be appreciated that the optimal route will vary with the condition and age of the recipient, and the disease being treated. The term “effective amount” refers to a quantity sufficient to achieve a desired effect. In the context of therapeutic or prophylactic applications, the effective amount will depend on the type and severity of the condition at issue and the characteristics of the individual subject, such as general health, age, sex, body weight, and tolerance to pharmaceutical compositions. With respect to immunogenic compositions, in some embodiments the effective amount will depend on the intended use, the degree of immunogenicity of a particular antigenic compound, and the health / responsiveness of the subject's immune system, in addition to the factors described above. The skilled artisan will be able to determine appropriate amounts depending on these and other factors. -57- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In the case of an in vitro application, in some embodiments the effective amount will depend on the size and nature of the application in question. It will also depend on the nature and sensitivity of the in vitro target and the methods in use. The skilled artisan will be able to determine the effective amount based on these and other considerations. The effective amount may comprise one or more administrations of a composition depending on the embodiment. “Simultaneous use” as used herein refers to the administration of the two compounds of the composition according to the disclosure in a single and identical pharmaceutical form or at the same time in two distinct pharmaceutical forms. “Separate use” as used herein refers to the administration, at the same time, of the two compounds of the composition according to the disclosure in distinct pharmaceutical forms. “Sequential use” as used herein refers to the successive administration of the two compounds of the composition according to the disclosure, each in a distinct pharmaceutical form. The term “tissue” is used herein to refer to tissue of a living or deceased organism or any tissue derived from or designed to mimic a living or deceased organism. The tissue may be healthy, diseased, and / or have genetic mutations. The biological tissue may include any single tissue (e.g., a collection of cells that may be interconnected) or a group of tissues making up an organ or part or region of the body of an organism. The tissue may comprise a homogeneous cellular material or it may be a composite structure such as that found in regions of the body including the thorax which for instance can include lung tissue, skeletal tissue, and / or muscle tissue. Exemplary tissues include, but are not limited to those derived from liver, lung, thyroid, skin, pancreas, blood vessels, bladder, kidneys, brain, biliary tree, duodenum, abdominal aorta, iliac vein, heart and intestines, including any combination thereof. As used herein, “treating” or “treatment of” a condition, disease or disorder or symptoms associated with a condition, disease or disorder refers to an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but -58- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of condition, disorder or disease, stabilization of the state of condition, disorder or disease, prevention of development of condition, disorder or disease, prevention of spread of condition, disorder or disease, delay or slowing of condition, disorder or disease progression, delay or slowing of condition, disorder or disease onset, amelioration or palliation of the condition, disorder or disease state, and remission, whether partial or total. “Treating” can also mean prolonging survival of a subject beyond that expected in the absence of treatment. “Treating” can also mean inhibiting the progression of the condition, disorder or disease, slowing the progression of the condition, disorder or disease temporarily, although in some instances, it involves halting the progression of the condition, disorder or disease permanently. Thus, in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. In certain non-limiting embodiments, the condition, disease, or disorder capable of being treated by the aspects disclosed herein is an autoimmune or fibrotic disorder, disease, or condition, proinflammatory condition, or an aberrant immune response. In certain embodiments, the autoimmune or fibrotic disorder, disease, or condition, proinflammatory condition, or an aberrant immune response is selected from the group consisting of polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still’s disease, adult-onset Still’s disease, amyloid A amyloidosis, polymyalgia rheumatic, -59- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet’s disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug-Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent),, allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener’s granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn’s disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, -60- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto’s thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison’s disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. The term “prevent” refers to a decrease in the occurrence of a disease or disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment. In one aspect, the term “treatment” excludes “prevention.” In one embodiment, the term “disease” or “disorder” as used herein refers to allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation. In one embodiment, the term “disease” or “disorder” as used herein refers to a status of being diagnosed with allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation, a status of being suspect of having allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation, or a status of at high risk of having allergy (optionally, a food allergy or an allergic reaction), hypersensitivity, asthma, inflammatory response or inflammation. As used herein, a “symptom” of a disease includes any clinical or laboratory manifestation associated with the disease and is not limited to what a subject can feel or observe. The compositions used in accordance with the disclosure can be packaged in dosage unit form for ease of administration and uniformity of dosage. The term "unit dose" or "dosage" refers to physically discrete units suitable for use in a subject, each unit containing a -61- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 predetermined quantity of the composition calculated to produce the desired responses in association with its administration, i.e., the appropriate route and regimen. The quantity to be administered, both according to number of treatments and unit dose, depends on the result and / or protection desired. Precise amounts of the composition also depend on the judgment of the practitioner and are peculiar to each individual. Factors affecting dose include physical and clinical state of the subject, route of administration, intended goal of treatment (alleviation of symptoms versus cure), and potency, stability, and toxicity of the particular composition. Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described herein. As used herein, the term “single chain antibodies” refer to antibodies formed by recombinant DNA techniques in which immunoglobulin heavy and light chain fragments are linked to the Fv region via an engineered span of amino acids. Various methods of generating single chain antibodies are known, including those described in U.S. Pat. No. 4,694,778; Bird, Science 242:423-442 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879- 5883 (1988); Ward et al., Nature 334:54454 (1989); Skerra et al., Science 242:1038-1041 (1988). As used herein, the term “specifically binds,” with respect to an antibody, means an antibody or binding fragment thereof (e.g., Fv fragment or scFv) which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more species. But, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, a chimeric antigen receptor, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic -62- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 determinant or epitope) on the chemical species; for example, a chimeric antigen receptor recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A,” the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least about 20 contiguous positions, usually 30 to about 75, 40 to about 50, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, Wis.), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M. O. (1978) A model of evolutionary change in proteins— Matrices for detecting distant relationships. In Dayhoff, M. O. (ed.) Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington D.C. Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogeny pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, Calif.; Higgins, D. G. and Sharp, P. M. (1989) CABIOS 5:151-153; Myers, E. W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E. D. (1971) Comb. Theor 11:105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P. H. A. and Sokal, R. R. (1973) Numerical Taxonomy—the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, Calif.; Wilbur, W. J. and Lipman, D. J. (1983) Proc. Natl. Acad., Sci. USA 80:726-730. -63- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Alternatively, optimal alignment of sequences for comparison may be conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group (GCG), 575 Science Dr., Madison, Wis.), or by inspection. One particular example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. BLAST and BLAST 2.0 can be used, for example, with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides of the disclosure. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. The rearranged nature of an antibody sequence and the variable length of each gene requires multiple rounds of BLAST searches for a single antibody sequence. Also, manual assembly of different genes is difficult and error-prone. The sequence analysis tool IgBLAST (world-wide-web at ncbi.nlm.nih.gov / igblast / ) identifies matches to the germline V, D and J genes, details at rearrangement junctions, the delineation of Ig V domain framework regions and complementarity determining regions. IgBLAST can analyze nucleotide or protein sequences and can process sequences in batches and allows searches against the germline gene databases and other sequence databases simultaneously to minimize the chance of missing possibly the best matching germline V gene. In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST -64- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments, (B) of 50, expectation (E) of 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity. In some embodiments, the Fv fragment further comprises a linker domain to generate a single chain variable fragment (scFv). In one embodiment, the linker domain is operably linked to the heavy chain variable domain and the light chain variable domain. In some embodiments, the light and heavy chain variable regions are contiguously linked via a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide, and the scFv retains the specificity of the intact antibody from which it is derived. In one embodiment, the -65- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 flexible polypeptide linker includes, but are not limited to, (Gly4 Ser)4 or (Gly4 Ser)3. In another embodiment, the linker includes multiple repeats of (Gly2Ser), (GlySer) or (Gly3Ser). Modes for Carrying Out the Disclosure Therapeutic Methods Provided herein are methods for treating an autoimmune disease or a fibrotic disease in a subject, the method comprising, consisting of, or consisting essentially of administering to the subject an effective amount of an agent to modulate the activity of a population of T-cells expressing one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject. Provided herein are methods for treating an autoimmune disease or a fibrotic disease in a subject, the method comprising, consisting of, or consisting essentially of administering to the subject an effective amount of an agent that modulates expression in T cells of one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject. In some aspects, T-cells are CD4+ or CD8+ T-cells. In some aspects, the agent is selected from a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. In some aspects of this disclosure, the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding one or more of the targets identified herein. In some aspects, administration of the agent induces higher or lower than baseline expression of the one or more of the targets in T-cells. In some aspects of this disclosure, higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression. In some aspects, higher than baseline expression of the one or more genes is at least about a 0.5-fold increase in -66- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 0.5-fold decrease in expression relative to baseline expression In some aspects of this disclosure, baseline expression comprises normalized mean gene expression. For example, the obtained raw gene expression data may be adjusted to account for various sources of technical variation, allowing for accurate comparison of gene expression levels across different samples or conditions. Methods for normalization may include, but are not limited to, total count normalization, upper quartile normalization, trimmed mean of M values normalization, quantile normalization, or normalization to a reference gene. In some aspects, the methods further comprise, consist of, or consist essentially of administering to the subject an additional therapy for the autoimmune disease or the fibrotic disease. In some aspects, the autoimmune disease or fibrotic disease comprises polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatic, Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug- Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, -67- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin- dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. In some aspects, the autoimmune disease or fibrotic disease comprises ulcerative colitis, Crohn’s disease, or rheumatoid arthritis. -68- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In some aspects, the one or more targets are selected from: TIAM1, IGFBP4, IL21, IL21- R, PASK, TMEM155, HMOX1, CD81, CAV1, FCRL3, PGM2L1, and ICA1. Diagnostic Compositions and Combinations This disclosure also provides methods of diagnosing an autoimmune disease or fibrotic disease in a subject, the method comprising, consisting of, or consisting essentially of contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample isolated from the subject, wherein the presence of the one or more genes at higher or lower than baseline expression levels is a diagnostic indicator of the autoimmune or the fibrotic disease or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not diagnostic indicator of the autoimmune disease or fibrotic disease. Also provided is a method of identifying a subject that will or is likely to respond to one or more of an autoimmune therapy or a fibrotic disease therapy, the method comprising, consisting of, or consisting essentially of contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the autoimmune therapy or the fibrotic disease therapy. The presence or absence of the one or more of the targets refers to whether the specific target is found (present) or not found (absent) in a given location or sample. When absent, the target may be undetectable or present in an amount that is lower that a detectable limit, may not be present at all in the sample, or at the baseline expression levels. When present, the target may be detectable (i.e., produce a detectable signal such as through absorbance, fluorescence, luminescence, radioactivity, etc.) and measurable (e.g., inducing a measurable change in an assay). -69- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In an aspect, baseline expression is normalized mean gene expression for the assayed genes. In some aspects of the present disclosure, higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression relative to baseline expression. In some aspects, higher than baseline expression of the one or more genes is at least about a 0.5-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 0.5- fold decrease in expression relative to baseline expression In some aspects, the methods further comprise, consist of, or consist essentially of administering to a patient in need thereof an autoimmune therapy or a fibrotic disease therapy to the subject. In some aspects of the disclosure, the autoimmune therapy or the fibrotic disease therapy is one or more of hormonal therapy, immunotherapy, or monoclonal antibody therapy. In some aspects, the sample is contacted with an agent, optionally including a detectable label or tag. In some aspects of the disclosure, the detectable label or tag comprises a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. In some aspects, the agent comprises a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene. In some aspects of the disclosure, the polypeptide comprises an antibody, an antigen binding fragment thereof, or a receptor that binds to the gene. In some aspects of the disclosure, the antibody is an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. In some aspects of the disclosure, the IgG is an IgG1, IgG2, IgG3 or IgG4. In some aspects of the disclosure, the antigen binding fragment is a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. -70- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In some aspects, the agent is contacted with the sample in conditions under which it can bind to the one or more targets. In some aspects, the method comprises detection of an antibody-protein product by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. In some aspects, the sample comprises cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. In some aspects, the autoimmune disease or fibrotic disease comprises polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing, polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatic, Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug- Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum -71- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin- dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. In some aspects, the autoimmune disease or fibrotic disease comprises ulcerative colitis, Crohn’s disease, or rheumatoid arthritis. -72- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In some aspects, the one or more targets are selected from: TIAM1, IGFBP4, IL21, IL21- R, PASK, TMEM155, HMOX1, CD81, CAV1, FCRL3, PGM2L1, and ICA1. Therapeutic Compositions and Combinations This disclosure also provides a composition or combination of active agents comprising, or consisting essentially of, or yet further consisting of an effective amount of an agent to modulate the activity of a population of T-cells expressing one or more of the targets identified herein. Also provided is a composition or combination of active agents comprising, or consisting essentially of, or yet further consisting of an effective amount of an agent that modulates expression in T cells of one or more of the targets identified herein. The active agents can further comprise an additional therapeutic agent (examples of such are described herein) a carrier such as a pharmaceutically acceptable carrier and can be formulated in combination or separately, for concurrent or sequential administration. In one aspect, the compositions are formulated with one or more pharmaceutically acceptable excipients, diluents, carriers and / or adjuvants. In addition, embodiments of the compositions of the present disclosure include one or more of an isolated polypeptide disclosed herein, an isolated polynucleotide disclosed herein, a vector disclosed herein, a small molecule, an isolated host cell disclosed herein, or an antibody of the disclosure, formulated with one or more pharmaceutically acceptable substances. In some aspects, the agent is selected from a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. For oral preparations, any one or more of an agent as described herein, a small molecule as described herein, an antibody as described herein, a lentivirus as described herein, an adeno- associated virus as described herein, an antisense oligonucleotide as described herein, an siRNA as described herein, an miRNA as described herein can be used alone or in pharmaceutical formulations disclosed herein comprising, or consisting essentially of, the compound in combination with appropriate additives to make tablets, powders, granules or capsules, for -73- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. Pharmaceutical formulations and unit dose forms suitable for oral administration are particularly useful in the treatment of chronic conditions, infections, and therapies in which the patient self-administers the drug. In one aspect, the formulation is specific for pediatric administration. Aerosol formulations provided by the disclosure can be administered via inhalation and can be propellant or non-propellant based. For example, embodiments of the pharmaceutical formulations disclosed herein comprise a compound disclosed herein formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like. For administration by inhalation, the compounds can be delivered in the form of an aerosol spray from a pressurized container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer. A non-limiting example of a non-propellant is a pump spray that is ejected from a closed container by means of mechanical force (i.e., pushing down a piston with one’s finger or by compression of the container, such as by a compressive force applied to the container wall or an elastic force exerted by the wall itself, e.g., by an elastic bladder). -74- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Suppositories disclosed herein can be prepared by mixing an active agent disclosed herein with any of a variety of bases such as emulsifying bases or water-soluble bases. Embodiments of this pharmaceutical formulation of a compound disclosed herein can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature. Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more the active agents disclosed herein. Similarly, unit dosage forms for injection or intravenous administration may comprise an active agent disclosed herein in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier. The composition or combination can be formulated for delivery by a continuous delivery system. The term “continuous delivery system” is used interchangeably herein with “controlled delivery system” and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art. Mechanical or electromechanical infusion pumps can also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, delivery of a compound disclosed herein can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. In some embodiments, a compound disclosed herein is in a liquid formulation in a drug- impermeable reservoir, and is delivered in a continuous fashion to the individual. -75- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Drug release devices suitable for use in the disclosure may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incorporated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc. Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present disclosure. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; and the like. In general, a subject treatment method can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems may be utilized due to their generally more consistent, controlled release over time. Osmotic pumps are used in some embodiments due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT International Application Publication No. WO 97 / 27840 and U.S. Pat. Nos. 5,985,305 and 5,728,396). Exemplary osmotically-driven devices suitable for use in the disclosure include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like. A further exemplary device that can be adapted for the present disclosure is the Synchromed infusion pump (Medtronic). In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in the art. As noted herein, an implantation site is a site within the body of a subject -76- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject’s body. Suitable excipient vehicles for a compound disclosed herein are, for example, water, saline, dextrose, glycerol, ethanol, or the like, and combinations thereof. In addition, if desired, the vehicle may contain minor amounts of auxiliary substances such as wetting or emulsifying agents or pH buffering agents. Methods of preparing such dosage forms are known, or will be apparent upon consideration of this disclosure, to those skilled in the art. See, e.g., Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17thedition, 1985. The composition or formulation to be administered will, in any event, contain a quantity of the compound adequate to achieve the desired state in the subject being treated. Compositions of the present disclosure include those that comprise a sustained-release or controlled release matrix. In addition, embodiments of the present disclosure can be used in conjunction with other treatments that use sustained-release formulations. As used herein, a sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid-based hydrolysis or by dissolution. Once inserted into the body, the matrix is acted upon by enzymes and body fluids. A sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (copolymers of lactic acid and glycolic acid), polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxcylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone. Illustrative biodegradable matrices include a polylactide matrix, a polyglycolide matrix, and a polylactide co-glycolide (co-polymers of lactic acid and glycolic acid) matrix. Experimental Examples -77- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Example 1: Stem-like T cells infiltrate colonic tissue of ulcerative colitis (UC) patients Applicant analyzed the single-cell transcriptomes of sorted T cells isolated from endoscopically inflamed and non-inflamed colonic tissue samples of patients from both sexes with active UC that were naïve to biological treatment modes (FIG. 1A). As controls, Applicant included colonic T cells from healthy subjects and UC patients in remission, and Applicant confirmed the quality of the data. This allowed Applicant to define associations that are specific to disease activity, which would be enriched only in the inflamed colonic tissues. Cellular indexing of transcriptomes and epitopes (CITE)-seq was also used to label cells expressing CD4 or CD8α. The CD4+and CD8α+T cells populations were well separated, although a few CD4+T cells in the intestine also expressed CD8α, consistent with other findings. Based on aggregation of the single cell transcriptomes of T cells from healthy subjects and UC patients, Applicant identified four main CD8+T cell subsets including (FIG. 1B): (i) Five clusters of tissue-resident memory T cells (TRM), (ii) TC17 cells, enriched for the expression of IL17A, RORC and IL23R (cluster 8), and (iii) two GZMK-enriched subsets (clusters 2 and 13). One of these GZMK-enriched subsets (cluster 13) displayed significant enrichment of gene signatures linked to the autoimmune stem-like progenitor T cells previously characterized in mouse models (FIG. 1C). Notably, transcripts encoding TCF1 (TCF7) and PD-1 (PDCD1), markers of the previously reported autoimmune stem-like T cells, were significantly increased in this subset (FIG. 1D). This subset also showed enrichment of TFHsignature genes (PDCD1, CXCR5, CXCL13), another feature of autoimmune stem-like T cells that distinguishes them from other populations, such as conventional central memory T cells (TCM). Applicant identified six subsets of colonic CD4+T cells combined from the four colonic tissue sources (FIG. 1B), including TH17, regulatory T cells (TREG), TFH, and TITGA1, enriched for transcripts that encode the integrin α1 subunit. Integrins containing this subunit bind extracellular membrane proteins and are important for T cell activation and tissue homing. Among colonic CD4+T cells there also were two subsets (clusters 0 and 6) that were highly enriched for stem-like transcriptional signatures, including TCF7 and CD27 (FIG. 1E). -78- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 However, cluster 6, labeled as TCM, also was highly enriched for CCR7 and SELL transcripts that mark naïve and conventional TCM cells, although transcripts encoding CD69, CD154 and LTb also were increased. Cluster 0 was enriched for expression of TFHsignature genes (CXCR5, CXCL13, IL21) as well as transcripts encoding PD-1. Applicant provides results from a re-analysis of published datasets of ileal and colonic T cells from CD patients (FIG. 1F and FIG. 1G). Together, these data support a potential role of TSCin the pathogenesis of CD with ileal and colonic involvement. Applicant’s in silico analysis detected intestinal CD4+and CD8+T cells that were significantly enriched for the TSC gene signatures of UC colonic T cells in both biologic naïve and TNF blocker treated CD patients (FIG. 1F and FIG. 1G), which indicates that biological treatment was not having a major impact on TSC. Notably, key genes linked to TSC such as TCF7 ,PDCD1, CXCL13, CXCR5, CD27 showed similar expression pattern in CD4+and CD8+TSC from both UC and CD (FIG. 1H). Because autoimmune stem-like T cells are not well-characterized in human autoimmune diseases, Applicant explored published single-cell datasets in UC patients to validate the findings in other cohorts. Applicant found that colonic T cell subsets from other UC cohorts displayed increased expression of genes linked to the stem-like CD4+and CD8+T cells, i.e., stem-like T cells were also present in these UC patients, although they were not originally identified. Notably, in these studies, it was reported that such colonic T cell subsets, identified by other names, were increased in diseased tissue. Together, the analyses revealed populations of human colonic CD4+and CD8+T cells, including ones that resembled the autoimmune stem-like progenitor T cells observed in mouse models of autoimmunity, infection, allograft rejection, and cancer. Example 2: Stem-like CD8+T cells were increased in inflamed colonic tissue To explore associations between stem-like colonic T cells and UC disease states, Applicant separately examined the frequency of stem-like colonic CD8+T cells in each of the four tissue sources representing different states of inflammation and underlying disease. Stem- -79- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 like CD8+T cells were an infrequent population (mean frequency = 0.3%; FIG. 2A) in colonic tissue samples from healthy controls, in UC patients in remission, and from endoscopically non- inflamed sites of patients with active UC. In UC active inflamed samples, however, Applicant found a nearly 10-fold increase in the frequency of stem-like CD8+T cells (mean frequency = 5.3%). This selective increase highlighted a strong association of CD8+stem-like T lymphocytes with active inflammation in the colon of UC patients. Compared to the remainder of the colonic CD8+T cells from the four tissue sources as a group (FIG. 2B), or to the other CD8+T cell clusters individually (FIG.2C), the stem-like CD8+T cells were enriched for expression of transcripts encoding co-stimulatory molecules including CD27, a TNF receptor superfamily member (TNFRSF7), and CD28, part of the Ig superfamily. These proteins are known to be progressively down-regulated following CD8+T cell effector differentiation. Thus, unlike the other colonic CD8+T cell subsets, stem-like CD8+T cells were likely to maintain their responsiveness to co-stimulatory signals that drive proliferation and persistence. CD27 also marks the autoimmune stem-cell like TH17 cells present in an experimental autoimmune encephalomyelitis (EAE) model. Transcripts encoding another important co-stimulatory molecule, 4-1BB, encoded by TNFRSF9, were also enriched in stem- cell CD8+T cells (FIG. 2B). Because 4-1BB is upregulated following TCR stimulation, TNFRSF9-expressing stem-like CD8+T cells may be a population that is actively responding to antigen stimulation in UC active inflamed tissue. Stem-like CD8+T cells were also enriched for several transcripts encoding for molecules that enhance TCR signaling, including CD81 and CAVEOLIN-1(CAV or CAV1) (FIG. 2B). They also were enriched for the expression of transcripts encoding co-inhibitory molecules, such as PD-1, TIM-3 and LAG-3, that are expressed by T cells following persistent antigen stimulation. Although in the context of chronic viral infections T cells expressing these co-inhibitory proteins display dysfunctional features, in autoimmune disease models, T cells expressing them maintain their effector potential and drive inflammation. Together, these features of their gene expression program suggested that stem- like CD8+T cells had properties that permitted proliferation and self-renewal in the presence of persistent antigenic stimulation in the colon of patients with UC. -80- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Example 3: CD8+effector T cell populations were related to stem-like T cells Applicant found that the CD8+TRM subset was significantly reduced in UC active inflamed tissue. Although Applicant enriched for LP T cells, some of the CD8+TRMclusters (3 and 12), had increased transcripts for FCERG1, LAT2, and several NK receptors, typical of intraepithelial subsets in mice with potential protective function. Two other CD8+T cell populations with pathogenic effector properties were increased in inflamed tissue samples. A TC17 subset also displayed features linked to persistent antigen stimulation, such as expression of PDCD1, LAG3, HAVCR2, TNFRSF9. Unlike the stem-like CD8+T cells, however, TC17 cells lacked increased expression of transcripts linked to progenitor function, but instead displayed transcripts linked to effector functions, including pro-inflammatory molecules (IL17A, TNF, IFNG, IL26, CCL20, CCL4, CCL5) and cytotoxicity-associated molecules (GZMB, GZMA, and PRF1) (FIG. 2D). Consistent with previous studies, a subset of GZMKhighCD8+T cells (TGZMK) was present in the colonic tissues in all four groups, but was increased in UC active inflamed tissue. The TGZMK subsets expressed a high level of EOMES (FIG. 2D), a transcription factor shown to enhance the pathogenicity of CD8+T cells in a colitis model. These transcripts were found not only in cluster 13 stem-like T cells, but also in cluster 2, without stem-like features. A recent study in patients with rheumatoid arthritis also highlights the pathogenic potential of a TGZMK subset as key effectors driving disease. Thus, TC17 and TGZMK are two well-described pathogenic CD8+T cell effectors enriched in the inflamed tissues and could be important drivers of autoimmune disease. Investigations in autoimmune disease models suggest stem-like populations are essential for sustaining short-lived effectors and driving persistent inflammation. Therefore, Applicant used TCR sequence analysis to assess if clonal relationships existed between stem-like CD8+T cells and effector subsets (TC17 and TGZMK) in the inflamed colonic tissue from patients with active UC. Nevertheless, Applicant identified expanded clonotypes as those detected more than once in a patient. There were 1,572 TCR sequences from inflamed regions of patients with active UC (FIG. 2E), these were predominantly in the pathogenic TC17 and TGZMK subsets. Although it is challenging to determine progenitor relationships, because the number of cells that -81- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 can be sampled in diseased tissue from a single patient (median = 345 cells / subject) was limited, in six patients with active UC, eight of the 33 expanded clonotypes in CD8+T cells were shared between stem-like CD8+T cells and the potentially pathogenic cells, either the TC17 or TGZMKeffector subsets (FIG. 2E and FIG. 2F). This indicated clonal relationships between these subsets at an individual T cell and patient level. Therefore, the stem-like CD8+T cells may be precursors that sustained colonic pro-inflammatory effector subsets in UC patients. Example 4: Stem-like CD4+T cells were clonally related to TH17 cells Similar to stem-like CD8+T cells, stem-like CD4+T cells drive pathogenic TH17 cells in mouse models of central nervous system autoimmunity. These CD4+T cells express increased TCF1 and CD27, and are enriched for gene expression signatures associated with both stem-like CD8+T cells and TFH cells. Stem-like T cells with increased Tcf7 transcripts also are present in a mouse model of colitis. In patients with UC, Applicant found a population of colonic CD4+T cells that was significantly enriched for both stem-like and TFHgene signatures (FIG. 1C), and therefore perhaps similar to the stem-like CD4+T cells reported in the experimental autoimmune encephalomyelitis (EAE) models. The frequency of these stem-like CD4+T cells was significantly increased (9-fold) in inflamed tissues compared to other tissue sources, including non-inflamed tissue samples from the same patients (FIG. 3A). TCF1 binds to the Bcl6 promoter in mice to initiate the TFH gene expression programs, and it controls BCL-6 expression in different contexts in T lymphocytes. A previous study shows the importance of the transcription factor BCL-6 in promoting the progenitor and stem- like program induced by TCF1. Immunohistochemical staining showed that CD4+T and CD8+T cells expressing BCL-6 were increased in the inflamed colonic tissue of active UC patients. Because BCL-6 plays a key role in the establishment of the TFHgene expression program in CD4+T cells, it is perhaps not surprising that stem-like CD4+T cells display expression of prominent TFH genes, and hence are in the TFH category in previous publications. Notably, there are several reports of an increased frequency of TFHor TFH-like cells in the blood and colonic tissue of patients with active UC compared to healthy controls. However, these studies do not -82- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 link the colonic TFH-like cells to stem-like T lymphocytes, nor do they assess the potential progenitor function TFH cells for pathogenic effector CD4+T cell subsets. A single-cell trajectory analysis of CD4+T cells revealed a pathway linking the stem-like CD4+T cells with TH17 cells through an intermediary population (FIG. 3B). This intermediary population (TINT) shared transcriptional features with both TH17 cells (IL17A, RORC, CCR6, IL23R, CCL20) and stem-like CD4+T cells (CD27, CD28, TOX, TOX2, PDCD1, CXCR5, CXCL13) (FIG. 3C – FIG. 3E). When compared with the TH17 subset, cells in the TINTpopulation were less enriched for the expression of genes linked to proinflammatory function and cytotoxicity, consistent with a transitional state. Analysis of TCR sequences of the TINTpopulation from the UC active inflamed tissues showed overlap of several clonotypes between stem-like CD4+T cells and TH17 cells, indicating clonal relationships between these populations via an intermediary cell population (TINT) that showed extensive clonal sharing with stem-like T cells (FIG. 3F and FIG. 3G). Specifically, in six patients with active UC, 55 of the 65 expanded clonotypes in CD4+T cells from the inflamed colon tissue were shared between two of the three subsets (stem-like, TINT and TH17) in the same UC patient. Thus, similar to the findings on CD8+T cells, stem-like CD4+T cells may represent a progenitor population that sustained the pool of pathogenic effector CD4+T cells in inflamed tissue. To analyze if stem-like CD4+T cells influenced the CD8+T cells, Applicant examined the correlation between the frequencies of these cell types. Notably, Applicant found a strong positive correlation between the frequency of stem-like CD4+and stem-like CD8+T cells in UC active inflamed tissue, consistent with an interaction between them (FIG. 3H). Although several factors might influence this correlation, expression of IL21 transcripts were enriched in stem-like CD4+T cells (FIG. 3C – FIG. 3E) and IL21R transcripts were expressed by both stem-like CD8+T cells and TC17 cells. IL-21 has effects on both CD4 and CD8 T cells. Notably, it limits exhaustion and supports the maintenance of CD8+T cells in models of chronic viral infections. Therefore, Applicant suggest that IL-21 may serve similar functions and support the persistence of pathogenic stem-like CD8+T cells. -83- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 In an independent study of UC patients from Chile, Applicant confirmed an increased frequency of TCF1-protein expressing CD4+and CD8+T cells in inflamed colonic tissue (FIG. 3I and FIG.3J). Overall, the results supported an important role of stem-like CD4+T cells in driving UC pathogenesis by supporting other pathogenic colonic CD4+and CD8+T cell subsets. Example 5: BCL-6 deficiency attenuated the pathogenicity of CD4+T cells To investigate the role of the stemness / TFHgene expression program in driving the pathogenic functions of CD4+T cells, Applicant utilized the adoptive T cell-transfer model of colitis, by transferring naïve CD4+CD45RBhighCD25–T cells to Rag- / -mice. Because of the role of BCL-6 in promoting stemness / follicular gene expression programs, Applicant compared the pathogenicity of transferred BCL-6-deficient CD4+T cells, obtained from Bcl6fl / flCd4Cremice, to T cell controls from Bcl6fl / fllittermates (FIG. 4A). In agreement with an earlier study, Rag1- / -mice that received BCL-6-deficient cells displayed reduced colitis, with at most only transient weight loss (FIG. 4B), and significantly reduced tissue inflammation (FIG. 4C). At the experimental end point, the numbers of CD4+T cells in colon lamina propria (LP) were significantly reduced in Rag1- / -mice that received BCL-6-deficient CD4+T cells (FIG. 4D). The frequency of TH17 cells, measured as IL-17-producing CD4+T cells, was significantly reduced in mice receiving BCL-6-deficient CD4+T cells (FIG. 4E). The cytotoxic CD4+T cells, measured by co-expression of CD8αα, was also reduced significantly (FIG. 4E). In contrast, the percentages of IFNγ and IL-4 expressing CD4+T cells remained unchanged. Together, these results indicated that BCL-6 deficiency may have attenuated a stemness function, measured by the sustained increase in T cells in the inflamed colon tissue. Applicant analyzed the single-cell transcriptomes of CD4+colon LP T cells in the recipients to define the impact of BCL-6 deficiency on their gene expression programs in this colitis model (FIG. 5A). Trajectory analysis indicated a differentiation pathway that terminated in a cluster (cluster 4) that was highly enriched for TH17 signature genes, including IL17A and -84- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 IL22 (FIG.5B and FIG. 5C), and the TFH signatures (FIG. 5D), implying a dependency of TH17 differentiation on BCL-6. The TH17 population, however, was significantly reduced in the BCL- 6-deficient CD4+T cells (FIG. 5E). Trajectory analysis suggested a block in the development of the TH17 subset (FIG. 5B), although BCL-6 deficiency could also have impacted TH17 proliferation, homing or persistence in the colon. Another cluster (cluster 2), which was enriched for cytotoxic CD4+T cell features (Gzmk, Ccl5), also was significantly reduced in the BCL-6-deficient CD4+T cells (FIG.5E). Applicant notes that in short term in vitro culture assays, Bcl6fl / flCd4CreT cells were not impaired for the rapid induction of TH17 cells, which regardless, might not be the highly pathogenic TH17 subset. The requirement for repeated stimulation likely is an important aspect of BCL-6 function in driving TH17 pathogenic cells. Together Applicant showed that BCL-6 deficient CD4+T cells had a decreased population in the colon of the recipients, and a selective decrease in the differentiation of TH17 and CD4+CTL cells, both likely contributed to reduced pathogenicity. Because BCL-6 is also known to play a key role in TFH and other T cell differentiation programs, however, it was not possible to distinguish the effects that are specific to the TCF1-dependent stem-like program. Example 6: TCF1-deficiency attenuated pathogenicity of CD4+T cells The stem-like T cells observed in UC active inflamed tissue showed enrichment in the expression of TCF1-encoding transcripts (TCF7 gene). In an independent cohort of UC patients, Applicant confirmed an increased frequency of TCF1-expressing CD4+and CD8+T cells in the inflamed colonic tissue samples. Importantly, TCF1 is the key transcription factor that drives stem-like gene expression program in mouse T cells. To directly test the role of stem-like CD4+T cells in driving pathogenesis of colitis, Applicant employed two complementary approaches. First, Applicant performed loss-of-function studies using TCF1-deficient T cells. Applicant transferred CD4+T cells, obtained from Tcf7fl / flCd4Creor Tcf7fl / fllittermate mice, into separate cohorts of Rag1- / -mice (FIG. 6A). TCF1 deficiency significantly reduced the expansion of CD4+T cells in colon LP (FIG. 6B), although without influencing the proportion of CD4+T cell subsets that expressed CD8α, FOXP3, IFNγ or IL-17A. Consistent with the results using BCL- 6-deficient CD4+T cells, Rag1- / -mice that received TCF1-deficient cells displayed reduced -85- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 colitis, with decreased weight loss (FIG. 6C), and significantly reduced tissue inflammation (FIG. 6D). To reliably track live TCF1-expressing stem-like T cells in the recipient mice, Applicant transferred naïve CD4+T cells from Tcf7GFPreporter mice (FIG. 7A), in which GFP reliably reflected TCF1 expression, into Rag- / -mice. Naïve CD4+T cells were almost entirely GFP+, but Applicant detected both GFP+and GFPnegCD4+T cells in the mesenteric lymph nodes (mLN) and colon LP of recipient Rag- / -mice eight weeks after transfer (FIG. 7B). This finding suggested that GFP+T cells can self-renew and give rise to GFPnegCD4+T cells in the transfer colitis model. As expected, GSEA analysis of the bulk transcriptomes showed that the LP GFP+CD4+T cells were significantly enriched for stem-like signature genes while the GFPnegCD4+T cells were enriched for effector signature genes. To compare the relative pathogenicity of such stem-like CD4+T cells versus other CD4+T cells, in secondary transfer experiments, Applicant isolated TCF1-expressing (GFP+) and non- expressing (GFPneg) CD4+T cells from colon LP and secondary lymphoid organs (SLO, spleen and mLNs) from the primary Rag- / -recipient mice, and transferred them into separate cohorts of disease-free Rag- / -mice (FIG. 7A). Rag1- / -secondary recipient mice that received GFP+cells from either SLO or colon LP displayed more weight loss (FIG. 7C), and increased tissue inflammation (FIG. 7D) compared to those that received GFPnegCD4+T cells. Notably, transfer of a 5-fold lower number of TCF1-expressing cells resulted in significantly more weight loss in recipient mice compared to those that received GFPnegCD4+T cells (FIG. 7C). Consistently, the transferred GFP+CD4+T cells also showed a significantly greater population increase in colon LP when compared to GFPnegCD4+donor T cells (FIG. 7E and FIG. 7F). Together these results supported an important role of TCF1-expressing stem-like CD4+T cells in the pathogenicity of colitis in this mouse model. Example 7: Effects of CD4+T cells on CD8+T cells -86- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Based on findings in UC patients, Applicant hypothesized that CD4+T cells that are enriched in the UC active inflamed tissue are also likely to support the pathogenicity of CD8+T cells. Utilizing the T cell transfer colitis model, Applicant assessed the impact of CD4+T cells on CD8+T cells, by adoptively transferring these cell types separately or in combination (FIG. 8A). Transfer of total CD8+T cells alone did not lead to colitis (FIG. 8B) nor T cell expansion (FIG. 8C). This was perhaps due to the absence of CD4+T cell-derived cytokines that would have driven CD8+T cell proliferation. In contrast, when Applicant transferred 1 x 105CD4+T cells, a lower number than typical for pathogenesis in this model, with 5 x 105CD8+T cells, weight loss was significantly worsened in recipient mice, with a trend towards increased inflammation (FIG. 8B). Furthermore, while the number of CD4+T cells was not changed in the presence or absence of CD8+T cells, the number of colon LP CD8+T cells was increased >100 fold compared to recipient mice that received CD8+T cells only (FIG. 8C). The large increase in CD8+T cell number in the colon was accompanied by an increase in the percentage of colonic CD8+T cells producing IFNγ and Granzyme B, which provided an increased number of cells capable of contributing to pathogenesis. Notably, in this co-transfer colitis model, BCL-6- deficient CD8+T cells, obtained from Bcl6fl / flCd8aCremice, displayed significantly reduced expansion in the colon LP when compared to BCL-6-sufficient CD8+T cells (FIG. 8D and FIG. 8E). To determine the impact of BCL-6 deficiency on the stem-like gene expression program in transferred CD8+T cells, Applicant compared the single-cell transcriptomes of BCL-6-sufficient and BCL-6-deficient CD8+T cells (FIG. 8F). Clusters 1 and 2 that were enriched for the expression of stem-like signature genes, including Tcf7 (FIG. 8G and FIG. 8H), were reduced in the BCL-6-deficient CD8+T cells (FIG. 8F). The other major CD8+T cell subsets (clusters 0,3,4) were enriched for the expression of effector signature genes, including Klrg1 and Gzmb (FIG. 8G and FIG. 8H). Applicant confirmed at the transcript and protein level that Granzyme B expression levels, which reflected a more effector state, were significantly increased in transferred BCL-6-deficient CD8+T cells (FIG.8I and FIG. 8J). These findings supported a model in which CD4+T cells promoted the expansion and pathogenicity of CD8+T cells, and that BCL-6 expression in CD8+T cells supported the expansion of donor-derived CD8+T cells with stem-like features in the colon LP. -87- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Example 8: Spatial transcriptomic analysis In selected samples (at least 10 samples per cohort type) with a high frequency of TSC from protein analysis, the 10x Xenium platform is used (FIG. 9), to perform single-cell resolution spatial transcriptomic analysis followed by multiplex IF of selected markers on the same section. FIG. 9 illustrates spatial transcriptomic data using the Xenium 5000 gene panel on an inflamed colonic tissue sample from a UC patient. Single-cell data was generated from 86,824 cells (mean of 169 genes detected per cell with good quality), and unbiased clustering of cells resulted in the identification of 6 major cells types: T cells, B cells, myeloid cells, epithelial cells, fibroblasts and endothelial cells (FIG. 9). Applicant also illustrates TSC(TCF7-expressing T cells; red) and non-TSC(yellow) in these sections. Example 9: Genes enriched in TSCin CD TSC ‘candidate genes’ include surface molecules with increased transcript levels in human intestinal TSCand known to have immune modulating function, including for CD4+TSC: cell surface proteins PD-1, OX-40, TIGIT, and intra-cellular proteins BATF and TOX2; for CD8+TSC: cell surface proteins TIGIT, CRTAM and TIM3, and intra-cellular protein GZMK. For both CD4 and CD8 TSC: CD27, CXCL13, and TOX and the IL-21 pathway are relevant. Transcripts encoding IL-21 were enriched in CD4+ TSC cells and IL21R transcripts were present in CD8+ TSC (FIG. 10). Studies have shown that IL-21 promotes the effector properties of CD8+ T cells, and it supports the maintenance of CD8+ T cells in chronic viral infection models. In addition, FIG. 10 shows a few examples of novel TSC ‘candidate molecules’, less known or not previously known for the effects on immune function but with transcripts highly enriched in TSCfrom CD patients: (i) PASK is a member of the nutrient-regulated protein- serine kinase family that integrates metabolic and nutrient signals in embryonic stem cells (ESC), orchestrating their transition from self-renewal to a differentiated state. Notably, inhibiting PASK in ESCs increased their progenitor population, suggesting the potential of this molecule to modulate stemness in T cells. (ii) TMEM155 encodes a transmembrane protein; its murine -88- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 ortholog (Gm11549) encodes Nodal Enhanced Micropeptide (NEMEP). NEMEP enhances glucose uptake and differentiation of mouse ESCs. Notably, the peptide encoded by TMEM155 also interacts with glucose transporters. These two genes highlight that molecules with important functions in ESC are enriched in human Tsc. (iii) TIAM1, a critical upstream regulator of Rho- GTPase Rac1, which controls pathways involved in cytoskeletal dynamics, membrane trafficking, and metastasis. In an experimental autoimmune encephalomyelitis, TIAM1 enhanced transcription of Il17a in CD4+T cells, contributing to disease, consistent with genes that TSCmight require to transition to effectors. (iv) IGFBP4 (Insulin growth factor binding protein 4) is a key player in IGF signaling, regulating the local availability of IGF ligands. Notably, IGF signaling promotes differentiation of TH17 cells, alters their metabolic state and induces the expression of genes associated with pro-inflammatory functions. (v) HMOX1, encodes for heme oxygenase-1(HO-1) that displays properties, including anti-apoptotic function. Additionally, HO-1 impaired the effector function in CD8+T cells. (vi) CD81 enhance TCR signaling and FCRL3 signaling modulates TREG activity. (vii) A regulator of glucose metabolism PGM2L1 and another protein (ICA1) that has not been characterized in T cells. In addition to these examples, there are over 100 transcripts that are highly enriched in Tsc that also require functional testing to determine their role in Tsc generation and function. Example 10: CD4+TSCfunctional studies In the T cell transfer to Rag- / -mouse model of colitis, Applicant showed that loss of the key stem-like T cell transcription factor, TCF1 (encoded by Tcf7) in T cells, led to reduced T cells in the colon and reduced inflammation. A limitation of the experiment is that the CD4-Cre recombinase used disables Tcf7 in differentiating thymocytes, which may cause overall defects in T cell maturation. Applicant has more rigorously tested the function of TCF1 in mature T cells in colitis using the distal Lck-Cre (dLck) recombinase, which acts only in mature T cells. The data indicate that the later-acting dLck-Cre also provides partial protection from severe colitis (FIG. 11A – FIG. 11D) by deleting part of the Tcf7 gene to reduce TCF1, which was confirmed by flow cytometry (FIG. 12, left). The results confirm that TCF1 acts in mature T cells to sustain inflammation in this colitis model (FIG. 11A – FIG. 11D). -89- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Applicant has crossed of Tcf7f / fmice with tamoxifen-inducible Cd4Cre-ERT2mice and has confirmed by flow cytometry that tamoxifen treatment induces deletion of TCF1 in post-thymic T cells (FIG. 12, right). Example 11: CD8+T cell-dependent colitis model To assess pathogenicity of CD8+T cells, Applicant has further optimized the conditions for the novel adoptive T cell-co-transfer colitis model. Transfer of total CD8+T cells alone to Rag1- / -mice did not lead to CD8+cell proliferation or colitis. In contrast, when a limiting number (1 x 105) of CD4+T cells with 5 x 105CD8+T cells was transferred, weight loss and histology scores were reproducibly worsened compared to recipients of CD4+T cells alone (FIG. 13A- FIG.13D). Furthermore, the number of colon LP CD8+T cells reproducibly was increased >100 fold compared to recipient mice that received CD8+T cells only (FIG. 13B). Example 12: Discovery of TSCin other autoimmune diseases Applicant explored published single-cell datasets in UC patients to validate the findings. The in silico analysis detected TCF7-expressing colonic TSC in other UC cohorts, although they were not identified in those studies. In addition, T cells with TSC gene signatures were observed in tissue specimens from patients with CD and rheumatoid arthritis (FIG. 14). Example 13: Discussion of the Results Although they may encounter persistent antigen stimulation, pathogenic T cell populations are known to drive autoimmune inflammation without developing the dysfunctional features observed in models of chronic viral infections. Recent studies in animal models of autoimmune disease describe the existence of a stem-like T cell population that exhibits resistance to exhaustion, and importantly, this progenitor population sustains the pool of short- lived pro-inflammatory effector T cells that drive autoimmune inflammation. However, the characterization of such stem-like T cell populations that sustain pathogenic T cells and inflammation in human autoimmunity remains limited. By analyzing the transcriptomes of T -90- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 cell populations from the colon tissue of UC patients, Applicant identified CD8+and CD4+T cell populations in the inflamed regions that were enriched for gene signatures of the stem-like T cells reported in mouse models of autoimmunity and allograft rejection. Applicant found that similar T cell populations with stem-like features were present in publicly available single-cell datasets from UC patients. Notably, Applicant observed an expansion of the stem-like T cell populations in the inflamed colonic tissue of UC patients, and these cells were clonally related to the likely pathogenic T cell populations, including TH17, TC17 and TGZMKsubsets, which displayed pro-inflammatory properties. Based on these findings, Applicant hypothesized that stem-like T cells likely supported the persistence of these pathogenic effector cells, thereby contributed to persistent inflammation in the colon of UC patients. Stem-like T cells might not be the only source for pathogenic CD4+and CD8+T cells, and other clonal relationships that could contribute to pathogenesis were evident. For example, shared clones between CD8+TRM and TC17 cells were present, but Applicant note that it was the stem-like T cells that were enriched in inflamed regions of the colon. TCF1, a key transcription factor promoting the stem-like gene expression program, drives BCL-6 expression in T lymphocytes. BCL-6 is required for TFHdifferentiation, and although BCL6 transcripts were not well represented in sc-RNA-seq, Applicant found evidence for increased BCL-6 protein expression in UC active inflamed tissue. Furthermore, the CD4+stem- like T cells expressed genes typical of TFHcells, including IL21 transcripts. IL-21 promotes the formation of human TH17 cells in the presence of TGF-β and has been implicated as a possible cause of IBD. Therefore, it is possible that stem-like T cells contributed to pathogenesis in part through IL-21. Several studies have implicated TFHcells in UC pathogenesis, but the data suggested there were cells with varying degrees of stem-like and TFHfeatures, and Applicant propose that the stem-like cells provided the source for the other populations. To provide mechanistic confirmation of the role of the stem-like program in sustaining pathogenesis of colitis in mouse, Applicant transferred CD4+T cells that were deficient for either BCL-6 or TCF1. BCL-6 deficient CD4+T cells had a decreased population in the colon of the recipients, and a selective decrease in the differentiation of TH17 cells, both likely contributed to -91- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 reduced pathogenicity. CD4+CTL, which have been implicated in some mouse colitis models, also were selectively decreased with Bcl6fl / flCd4Credonor T cells. TCF1 acts upstream of BCL-6, and deficiency also impaired the expansion and pathogenicity of CD4+T cells. Functional effects on the transferred TCF1-deficient CD4+T cells were less evident, perhaps reflecting diverse functions of this transcription factor. In a secondary transfer model of colitis, Applicant confirmed that TCF1-expressing stem-like CD4+T cells displayed greater population expansion and colitis pathogenicity, thus supporting an important role of stem-like T cells in pathogenesis of colitis. Applicant used the T cell transfer model of colitis to show interactions between CD4+and CD8+T lymphocytes that might sustain the pathogenesis of colitis. Transferred CD4+T cells facilitated CD8+T cell population increase and homing to the intestine. The increased CD8+T cell population also had an increased frequency of T cells able to produce IFNγ and Granzyme B, and therefore could have contributed to disease. BCL-6 deficient CD8+T cells had a decreased population in the colon of the recipients, and showed impaired stemness gene signatures. Unlike chronic human IBD, which waxes and wanes, the mouse T cell transfer model of colitis is relentlessly progressive and rapidly fatal. Despite this, Applicant could show that the correlative findings in human IBD and the mechanistic findings from the mouse model are well aligned. Human IBD is heterogenous, classified into UC and CD, but with subtypes within these categories. Therefore, it is unlikely that IBD pathogenesis is due to a single T cell population that contributes to all TH17 cells or inflammatory CD8+T cells in every patient. In fact, there is evidence from some reports that although TH17 cells are increased in CD, that T lymphocytes in the colon of CD patients are different from those in UC, for example with increased CD4+TRMbut decreased TFHcells. It remains to be determined if these differences truly distinguish disease types, or reflect other factors, such as prior treatment, the site of the biopsy (ileum versus colon), ethnic group of the patients. Considering UC, overall, the studies in humans and mouse models support the importance of stem-like T cell populations in driving pathogenesis, and therefore approaches aimed at either monitoring or therapeutically targeting this population may hold promise in the clinic. -92- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Example 14: Methods and Materials Human samples and data. Written informed consent was obtained from all study participants. The study was approved by the United Kingdom South Central - Hampshire A Research Ethics Committee 10 / H0502 / 69. Colonic pinch biopsies were collected from subjects with and without UC who had a pre-arranged colonoscopy or flexible sigmoidoscopy outside of the study. Baseline patient and disease characteristics, medication history and disease scores were collected. UC patient biopsies were taken from endoscopically inflamed sigmoid colon, and when present and accessible from more proximal macroscopically non-inflamed colon and never known to be affected tissue. Sigmoid colon biopsies were also collected from patients in remission at sites of previous inflammation. Remission is defined as no patient reported flares for the prior 6 months, with Mayo score components (rectal bleeding = 0, stool frequency <= 1, endoscopy = 0). Healthy control samples were taken from patients without gastrointestinal symptoms who were undergoing endoscopic investigation for iron deficiency anemia or previous colonic polyps. Patients with a history of malignancy, polyposis syndrome or treatment with immunosuppression therapy were excluded. At least 2 colonic biopsies from each study subject were fixed in 10% neutral buffered formalin at 20°C for 24 hours, for histology processing. Up to a further 8 colonic biopsies from each site sampled were collected in Aquix RS-I on ice for immediate enzymatic disaggregation. Samples were agitated in 1ml RPMI medium with 0.15WU / mL Liberase DL and 800U / mL DNase at 37°C for 15 minutes. After filtering and centrifuging, the cells were resuspended in freezing buffer [10% (v / v) DMSO, 50% (v / v) complete RPMI, and 40% (v / v) FBS] and cryopreserved at −80°C then transferred to liquid nitrogen. For immunofluorescence analysis, samples were obtained from an independent cohort of patients diagnosed with UC and healthy controls who were scheduled for routine colonoscopy at Hospital Clínico San Borja, a tertiary referral center for Inflammatory Bowel Disease within the Chilean Public Health System. To ensure accurate UC diagnosis, Applicant carefully selected patients based on comprehensive assessments of clinical symptoms, endoscopic observations, histologic evaluations, and imaging findings. The patient selection process adhered to -93- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 established clinical guidelines and International Disease Classification criteria 51,52. Patients were enrolled in the study under the approved research protocol by the Servicio de Salud Metropolitano Central / HSBA (IRB:43 / 2022). Colon biopsies were collected and embedded in paraffin for further analysis. Mice. C57BL / 6J (stock no. 000664), Bcl6fl / fl(stock no. 023727), Rag1− / −(stock no. 002216), Tcf7GFPflox (stock no. 030909), Cd4Cre(stock no. 022071) and Cd8aCre(stock no. 008766) mice were obtained from the Jackson labs. All mice were between 6-14 weeks old at the beginning of the experiment. All mice were bred and housed under specific pathogen–free conditions in a standard 12-hour light / 12-hour dark cycle at 20°C and 50% humidity in the vivarium of La Jolla Institute for Immunology. Mice were fed standard rodent chow and water ad libitum. Age and sex-matched mice were used in all experiments, mice of both sexes were analyzed. Pairs or groups of mice used in each experiment were co-housed. All animal work was approved by the La Jolla institute for Immunology Animal Care and Use Committee. Adoptive T cell transfer model of colitis. Donor mouse spleens were harvested, mashed in complete RPMI medium (Gibco) (RPMI 1640 supplemented with 10% FBS and L- Glutamine-Pen-Strep Solution (GeminiBio), and filtered through 70µm cell strainers. Red blood cells were lysed using Red Blood Cell Lysing Buffer Hybri-Max (Sigma-Aldrich). Cells were enriched with MojoSort Mouse CD4 Naïve T Cell Isolation Kit and MojoSort Mouse CD8 T Cell Isolation Kit (BioLegend) and then stained with LIVE / DEAD Fixable Yellow Dead Cell Stain (Invitrogen) 1:300, anti-mouse CD4 (RM4-5), CD45RB (clone 16A), CD25 (clone PC61.5), TCRβ (clone H57-597), CD8β (clone eBioH35-17.2) 1:200 for each. Live CD4+CD45RBhighCD25−cells and TCRβ+CD8β+CD4−cells were sorted on a BD FACSAria cell sorter (BD Biosciences). In the naïve CD4+T cell transfer model, 2.5 x 105CD4+CD45RBhighCD25−T cells were injected into each Rag1- / -mouse retro-orbitally. In the co- transfer model, 1 x 105naïve CD4+CD45RBhighCD25–T cells and 5 x 105TCRβ+CD8β+CD4− T cells were injected into each Rag1- / -mouse. In the secondary transfer model, 2.5 x 105CD4+CD45RBhighCD25−T cells from the naive Tcf7GFPmice were injected into Rag1- / -mouse -94- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 retro-orbitally to induce colitis. 6-8 weeks later, GFP+or GFP–T cells were isolated from the spleen, mLN and LP of these Rag1- / -mouse, and transferred into separate cohorts of disease-free Rag1- / -mice. Mouse health symptoms, including hunching of the back and diarrhea, were monitored daily. Body weights of Rag1- / -mice were measured weekly and the mice were euthanized when they lost > 30% of their baseline weight loss or showed bad health conditions. Colons were harvested at the end of experiments. The middle part of colon was used for histological analysis. The colons were fixed with zinc formalin for 48 hours and then transferred to 70% isopropanol for long term storage or H&E staining. Rag1− / −mice were randomly assigned into different recipient groups. Mouse colonic tissue processing and cell isolation. Colons were collected from euthanized mice. Colons were opened longitudinally and rinsed in 1mM dithiothreitol (Sigma Aldrich) in PBS quickly to removed feces. Each colon was cut into 2-3mm pieces and collected in a 50 mL tube filled with 20 mL pre-digestion solution (1X HBSS containing 5% FBS and 2mM EDTA). Tubes were incubated at 37°C for 20 min under 250 rpm rotation to remove epithelial cells. Then tissues were minced with scissors and place into a 50 ml tube with 20 mL digestion solution (1X HBSS containing 5% FBS, 100 µg / mL DNase I (Sigma Aldrich) and 1 mg / mL collagenase (Sigma Aldrich)). Then tissues were digested at 37°C for 20 min under 250 rpm rotation. After incubation, cells were pelleted and then resuspended in 40% (v / v) Percoll (Cytiva) density gradient solution (in complete RPMI medium), and then layered over 80% (v / v) Percoll solution (in complete RPMI medium). Immune cells at the interface were collected after centrifugation at 800 x g for 20 minutes. Cells were washed and resuspended in staining buffer (PBS with 2% FBS and 2 mM EDTA) before further analysis. In vitro TH17 cell differentiation. Mouse spleens were harvested, mashed in complete RPMI medium, and filtered through 70µm cell strainers. Red blood cells were lysed using Red Blood Cell Lysing Buffer Hybri-Max (Sigma Aldrich). Cells were enriched with MojoSort Mouse CD4 Naïve T Cell Isolation Kit (BioLegend). 1 x 105cells were seeded into each well of a 96-well plate pre-coated with 2 µg / ml purified anti-mouse CD3ε antibody (Clone 145-2C11, BioLegend) in 200 µl mouse T cell culture medium (complete RPMI medium with 50 µM 2- -95- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 mercaptoethanol) with 2 µg / mL purified anti-mouse CD28 antibody (Clone 37.51) and TH17 cell polarization cytokines: 30 ng / mL recombinant mouse IL-6 (R&D Systems), 5 ng / mL recombinant human TGFβ (R&D Systems), 1 µg / mL anti-mouse IFNγ (clone XMG1.2), 1 µg / mL anti-mouse IL-4 (clone 11B11). 24h after activation, the supernatant was replaced with fresh T cell culture medium containing TH17 cell polarization cytokines. 3 days later, the supernatant was replaced with fresh T cell culture medium containing TH17 cell polarization cytokines and cells were cultured for another 3 days before analysis. Flow cytometry. Human T cells were prepared in staining buffer and human IgG (Sigma Aldrich) 1:50; mouse T cells were prepared in staining buffer and FcR blocking antibody (clone 2.4G2, BD Biosciences) 1:500. Surface proteins were stained with antibodies (1:400) as indicated below for 15 min at 4°C. Cell viability was determined using LIVE / DEAD Fixable Yellow Dead Cell Stain (Invitrogen) 1:300 or Propidium Iodide (Sigma Aldrich) 1:300. For cytokine staining, cells were treated with 50 ng / mL Phorbol 12-myristate 13-acetate (Sigma Aldrich), 500 ng / mL ionomycin (Sigma Aldrich) and 10 µg / mL Brefeldin A (Sigma Aldrich) for 4 hours. For intracellular cytokine staining or transcription factor staining, cells were fixed with Cytofix Fixation Buffer (BD Biosciences) and then stained with Foxp3 / Transcription Factor Staining Buffer Set (eBioscience). Antibodies for intracellular staining were diluted at 1:100. The following antibodies from BD Biosciences, BioLegend or eBioscience were used: anti- human CD3 (clone SK7), CD45 (clone HI30); anti-mouse CD4 (clone RM4-5), TCRβ (clone H57-597), CD8β (clone eBioH35-17.2), CD8β (clone 53-6.7), FoxP3 (clone FJK-16s), IL-17A (clone TC11-18H10), IFNγ (clone XMG1.2), Granzyme B (clone GB11), IL-4 (clone 11B11), TCF1 (clone S33-966), CD44 (clone IM7), CD62L (clone MEL-14); anti-GFP (clone FM264G). All samples were acquired on a BD LSR II flow cytometer or sorted on a BD FACS Aria cell sorter (both BD Biosciences) using FACS Diva 9.0., and analyzed using FlowJo 10.4.1. Immunohistochemistry. 5 µm sections of colon tissue were cut and mounted on TOMO hydrophilic adhesive microscope slides. Antigen retrieval was performed on a PT link machine with Dako Target Retrieval Solutions (S2367) at 65°C. Slides were then washed with Dako -96- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Wash Buffer (S3006) and left to come to 20°C. Staining was performed on a Dako Autostainer and cover-slipped with Dako glycergel mounting medium. Slides were first stained with registration CD31 DAB stain. Samples were then sequentially stained in the following order: CD8 (Clone C8 / 144B, Agilent) RTU, BCL-6 (Clone LN22, Leica) 1:30, and CD4 (Clone 4B12, Agilent) 1:100. Whole slide images were captured on a ZEISS Axio Scan.Z1 Slide Scanner (Carl Zeiss Microscopy GmbH). After scanning the slides were soaked in hot water 50°C to allow removal of the cover slide. Stain removal was then performed (50% ethanol, 2 min; 100% ethanol, 2 min; 100% xylene; 2 min, 100% ethanol, 2 min; and 50% ethanol, 2 min). The slides were then rehydrated in distilled water before repeating antigen retrieval and staining as above, with the order of antibodies used as above. Immunofluorescence Staining. For IBD patient colonic biopsies, tissue was fixed in 10% buffered formalin overnight and embedded in paraffin before sectioning at 4 µm and mounting on slides. Standard protocol for immunofluorescent staining was followed with minor modifications. Briefly, slides were rehydrated by baking for 1h at 60˚C and treated with Pro-par (PSL labs) and 100% alcohol and treated with antigen retrieval buffer (10 mM Tris 1 mM EDTA, pH 9.0) for 15 min at 110˚C. To reduce tissue autofluorescence, slides were placed in 4.5% H2O2 and 24 mM NaOH in PBS and illuminated with white light for 90 min followed at 20°C. Tissue sections were treated with 10% normal donkey serum (Jackson ImmunoResearch) and stained with the following antibodies in PBS-T at 4˚C overnight: anti-CD8α (Clone C8 / 144B, ThermoFisher) 1:400, anti-CD4 (Polyclonal AF-379-NA, R&D) 1:800, anti-TCF1 (Clone C63D9, CST) 1:400. Secondary antibodies donkey anti-goat AF488 (ThermoFisher), Donkey anti-mouse AF555 (ThermoFisher) and Donkey anti-rabbit CF750 (ThermoFisher) were all used at 1:500 at 4˚C overnight. Samples were counterstained with Hoechst at 1:1000 in PBS for 5 min at 20°C before mounting with Prolong Gold (ThermoFisher). Full slide scan was captured at 40X by AxioScan 7 Slide Scanner (Zeiss) and analyzed with QuPath v0.5.0 software. Bulk RNA seq assay. Purified mouse colonic LP T cells were stained with anti-mouse CD4 (clone RM4-5), TCRβ (clone H57-597), CD8β (clone eBioH35-17.2) at 1:200. Cell viability was determined using LIVE / DEAD Fixable Yellow Dead Cell Stain (Invitrogen). Live -97- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 TCRβ+CD8β-CD4+GFP+and TCRβ+CD8β-CD4+GFP–cells were sorted on BD FACSAria cell sorter (BD Biosciences) for bulk RNA-seq assay, as described above. RNA sequencing library was prepared using Smart-seq2 protocol. Libraries were subjected to 2 × 50-bp paired-end sequencing on an Illumina NovaSeq6000 (Illumina), generating at least 8 million uniquely mapped reads for each sample. Bulk RNA-seq data were mapped against mm10 reference genome using the in-house pipeline. Briefly, FASTQ data from sequencing was merged and filtered using fastp (v0.23.3), reads were aligned with the STAR aligner (2.7.10b), followed by further processing with samtools (v1.17), bamCoverage (v3.5.1), and Qualimap (v.2.2.2-dev). Raw and transcripts per million reads (TPM) counts were taken from STAR’s BAM aligned output. Single-cell transcriptome assay. Human T cells. Cryopreserved dispersed colonic tissue samples were thawed and resuspended in RPMI before being stained with fluorescently labeled anti-human CD3 (clone SK7) and CD45 (clone HI30) antibodies in addition to anti- human CD4 and CD8α CITE-seq antibody-oligonucleotide conjugates (BioLegend) and donor specific hashtag antibodies (BioLegend). All antibodies were diluted at 1:200. A maximum of 50,000 CD45+CD3+cells from up to 5 donors were flow cytometry sorted into low-retention, sterile and ice-cold collection tubes containing PBS: FBS (1:1 v / v) with RNase inhibitor (1:100). Sorted cells were processed using the 10x Genomics 5’ Tag v2 chemistry kit following the manufacturer’s instructions for single-cell RNA-seq, TCR sequencing and CITE-seq, and sequenced on an Illumina NovaSeq 6000 platform. Mouse T cells. Purified mouse colonic LP T cells were stained with anti-mouse CD4 (clone RM4-5), TCRβ (clone H57-597), CD8β (clone eBioH35-17.2) and TotalSeq™-C anti-mouse Hashtag Antibodies (BioLegend) at 1:200. Cell viability was determined using LIVE / DEAD Fixable Yellow Dead Cell Stain (Invitrogen). Live TCRβ+CD8β-CD4+or TCRβ+CD8β+CD4– cells were sorted on BD FACSAria cell sorter (BD Biosciences) for single-cell RNA-seq assay, as described above. Single-cell transcriptome and TCR analysis. Reads were retrieved with bcl2fastq (v2.20.0.422) and mapped to mm10 (v3.0.0) for mouse data and to hg19 (v3.0.0) for human data -98- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 using Cell Ranger’s (v3.1.0) count pipeline. Libraries were then aggregated by applying Cell Ranger’s aggr pipeline. Count matrices were processed using Seurat (v3.1.5) in R. Singlets were determined based on subject hashtags (TotalSeq-C) via the MULTIseqDemux function (autoThresh = TRUE and maxiter = 10) implemented in Seurat with the in-house pipeline. Briefly, using the UMI counts each cell barcode was labeled as a Doublet, a Negative (estimated to contain no cell), or a subject ID. A cell barcode was re-classified as doublets if the ratio of UMI counts between the top barcode and the next was lower than 3. Cells labeled as Doublet or Negative were removed from downstream analyses. Data from human cells were filtered as follows. Single cells were included for downstream analysis if they had a gene content between 300 and 3000, UMI counts between 500 and 9000, a percentage of mitochondrial counts lower than 15%, and a doublet score (Scrublet v0.2.3) lower than 0.3. A further round of filtering was performed by removing two low-quality clusters, a third cluster containing B cell markers, and a donor contributing only 3 cells. Genes present in 0.1% of the cells were excluded for downstream analysis. UMI counts were normalized to counts per 10,000, and log-transformed with a pseudocount (log[x+1]). Highly Variable Genes (HVG) were selected via the VST method excluding those with a mean expression lower than 0.01. The HVG that accounted for the top 20% of the standardized variance were included for principal component analysis (PCA). The expression matrix was further processed into a z-score-scaled subsetted HVG normalized and transformed matrix, where the cell cycling effect was regressed out with Seurat’s ScaleData function (vars.to.regress = nCount_RNA, percent.mt, S.Score, G2M.Score). This z-scored matrix was utilized to calculate the PCA and, using first 20 principal components, the neighborhood graph and UMAP (n.neighbors = 10). Clusters were calculated in the neighborhood graph via the Louvain community detection method. A resolution of 1.0 was chosen for cluster annotation. Applicant classified clusters as representing either CD4+T cells or CD8+T cells based on enrichment of the expression of either CD4 or CD8B transcripts, respectively. A small cluster of cells (cluster 15) was enriched for the expression of cell cycle genes, hence labeled as cycling cells. Clusters were labeled based on their enrichment for genes linked to specific T cell subsets (FIG. 1D and FIG. -99- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 1E). CD8+T cells in clusters 1,3,9,10,12 clustered together and shared TRM features, and hence were merged and labeled as CD8+TRM subset. Similarly, CD4+T cells in clusters 4 and 14 clustered together, shared similar features and were enriched for ITGA1 expression, hence merged as called a TITGA1 subset. Data from mouse cells were filtered in a similar manner. Firstly, cells labeled as Doublets were removed. Secondly, cells were included for downstream analysis if they had a gene content between 500 and 2700, UMI counts between 100 and 8500, a percentage of mitochondrial counts under 3%, and a Scrublet score lower than 0.4. The regression during the z-score-scaling only included nCount_RNA and percent.mt. Furthermore, another round of filtering was performed after removing low-quality, low-frequency (<1%), and non-T cell clusters. A cluster enriched for heat-shock proteins was removed during the second round of clustering analysis. The final clustering for mouse CD4+T cells had HVG accounting for ~20% of the variance, 20 principal components were used for UMAP and neighborhood graph, and a resolution of 0.4 was taken for cluster annotation. The final clustering for mouse CD8+T cells had HVG accounting for ~20% of the variance, 20 principal components were used for UMAP and neighborhood graph, and a resolution of 0.6 was taken for cluster annotation. Single-cell trajectory analysis. Monocle3 (v0.2.1) was applied to calculate the pseudotime with the number of UMI counts and percentage of mitochondrial counts in the residual_model_formula_str parameter. For consistency, the same highly variable genes from Seurat were used. A single partition for all cells was manually set, after which the cells were ordered into a cell trajectory that was projected on Seurat’s UMAP embedding. The cell trajectory’s origin was set using the get_earliest_principal_node function provided in Monocle3’s tutorial. For RNA velocity analysis cell Ranger’s BAM files per library were sorted with SAMtools (v1.8). These BAM files were used to create LOOM files containing spliced and unspliced matrices using velocyto’s run10x command. LOOM files were finally merged employing loompy’s (v3.0.6) combine function. Next, spliced / unspliced matrices were fed to CellRank (v1.2.0) to perform velocity analysis and produce the velocity embedding stream (smooth=0.8, min_mass=2). The same embedding derived from Seurat was used for this analysis. -100- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 GSEA and signature analysis. GSEA analysis was performed using fgsea(v1.10.1). Gene sets were translated between mouse and human names using biomaRt (v2.40.5). Normalized enrichment scores were calculated from the signal-to-noise ratio between compared groups. Signature module scores were calculated with Seurat’s AddModuleScore function. In brief, scores are construed by subtracting the mean of a random set of control genes from the mean of the signature gene set. This control list was the same size as the signature list. TCR analysis. Reads from 10x Genomics’ V(D)J TCR libraries were processed with the vdj pipeline from Cell Ranger to produce CDR3 sequences to identify clonotypes. The GRCh38 (v3.1.0) and GRCm38 (alts-ensembl-3.1.0) referenced were used. Briefly, V(D)J sequences were assembled for each library independently. Clonotype tables were then aggregated with the in-house script and combined with single-cell transcriptomics data. Clonotypes were defined by 10x Genomics Cell Ranger (v3.1.0): the set of productive Complementarity-Determining Region 3 (CDR3) sequences. Clone statistics (frequency and proportion) were calculated based on the aggregation, taking only cells present in the gene expression analysis. Clone sizes were defined as the number of cells sharing the same sequence for both TCRA and / or TCRB genes. Sharing of clonotypes by cells present in different clusters was illustrated using the UpSetR (Conway et al., 2017) R package and on UMAP embeddings (with ggplot2 v3.3.2). Analysis of published single-cell transcriptomic studies in UC cohorts. Gene expression matrix, cell and cluster annotations were downloaded from GSE125527, GSE148837 and Single Cell Portal SCP259, and transferred to the R statistical framework for analysis. Cells with low-quality transcriptomes, defined as cells expressing < 300 unique genes, < 200 total UMI content and > 10% of mitochondrial UMIs were excluded from further analysis. Principal component analysis (PCA) was then run on the variable genes (top 25%), and the first 25 principal components (PC) (Smillie et al) and 15 PC (GSE125527) were selected for downstream analyses based on the standard deviation of PCs (“elbow plot”). Cells were clustered using Seurat’s functions FindNeighbors and FindClusters with a resolution of 0.9 (Smillie et al) and 0.8 (GSE125527). Using cell annotation provided by the authors, Applicant determined the major T cell subset (annotated by the authors) present in each cluster. For GSE148837, -101- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Applicant utilized the clustering parameters provided by the authors. UMAPs are colored according to the normalized transcript counts of the genes of interest or gene signatures linked to stem-like CD8+and CD4+T cells identified in the dataset. Quantification and statistical analysis. No statistical methods were used to pre- determine sample sizes for the human study, but the sample sizes are similar to those reported in previous publications. Details regarding the number of samples or mice per group, replicates in independent experiments and statistical tests can be found in the figure legends. Sample sizes were based on published studies to ensure sufficient numbers of mice in each group for reliable statistical testing and accounting for variability. The sample sizes are indicated in the figure legends. For statistical analysis, all experiments, unless stated in figure legends, were performed at least two times independently. Statistical analyses were performed using GraphPad Prism 9. Normality tests were performed to determine the proper statistical methods. All the data met the assumptions of the statistical tests used. Data collection and analysis were not performed blind to the conditions of the experiments. No animals or data points were excluded from the analyses. Equivalents It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All nucleotide sequences provided herein are presented in the 5′ to 3′ direction. The embodiments illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” containing,” etc. shall be read expansively and -102- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure. Thus, it should be understood that although the present disclosure has been specifically disclosed by specific embodiments and optional features, modification, improvement and variation of the embodiments therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of particular embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure. The scope of the disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein. In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that embodiments of the disclosure may also thereby be described in terms of any individual member or subgroup of members of the Markush group. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control. In some aspect, the publication is referenced by an Arabic numeral. The present technology may include, but is not limited to, the features and combinations of features recited in the following embodiments, it being understood that the following -103- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 embodiments should not be interpreted as limiting the scope of the claims as appended hereto or mandating that all such features must necessarily be included in such claims: Embodiment 1: A method of treating an autoimmune disease or a fibrotic disease in a subject comprising administering to the subject an effective amount of an agent to modulate the activity of a population of T-cells expressing one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject. Embodiment 2: A method of treating an autoimmune disease or fibrotic disease in a subject comprising administering to the subject an effective amount of an agent that modulates expression in T cells of one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject. Embodiment 3: The method of embodiment 1 or embodiment 2, wherein the T-cells are CD4+ or CD8+ T-cells. Embodiment 4: The method of any one of embodiments 1–3, wherein the agent is selected from a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA. Embodiment 5: The method of embodiment 4, wherein the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding one or more of the targets identified herein. Embodiment 6: The method of any one of embodiments 2 to 5, wherein administration of the agent induces higher or lower than baseline expression of the one or more of the targets in T-cells. Embodiment 7: The method of embodiment 6, wherein higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression. -104- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Embodiment 8: The method of embodiment 6 or embodiment 7, wherein baseline expression comprises normalized mean gene expression. Embodiment 9: The method of any one of embodiments 1 to 8, further comprising administering to the subject an additional therapy for the autoimmune disease or the fibrotic disease. Embodiment 10: The method of embodiment 9, wherein the additional therapy comprises one or more monoclonal antibodies for the treatment of the autoimmune or the fibrotic disease. Embodiment 11: A method of diagnosing an autoimmune disease or fibrotic disease in a subject, comprising contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample isolated from the subject, wherein the presence of the one or more genes at higher or lower than baseline expression levels is a diagnostic indicator of the autoimmune or the fibrotic disease or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not diagnostic indicator of the autoimmune disease or fibrotic disease. Embodiment 12: A method of identifying a subject that will or is likely to respond to one or more of an autoimmune therapy or a fibrotic disease therapy, comprising contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the autoimmune therapy or the fibrotic disease therapy. Embodiment 13: The method of embodiment 12, wherein baseline expression is normalized mean gene expression for the assayed genes. Embodiment 14: The method of embodiment 13, wherein higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to -105- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression relative to baseline expression. Embodiment 15: The method of any one of embodiments 11–14, further comprising administering to a patient in need thereof an autoimmune therapy or a fibrotic disease therapy to the subject. Embodiment 16: The method of embodiment 15, wherein the autoimmune therapy or the fibrotic disease therapy is one or more of hormonal therapy, immunotherapy, or monoclonal antibody therapy. Embodiment 17: The method of any one of embodiments 11 to 16, wherein sample is contacted with an agent, optionally including a detectable label or tag. Embodiment 18: The method of embodiment 17, wherein the detectable label or tag comprises a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin. Embodiment 19: The method of embodiment 17 or embodiment 18, wherein the agent comprises a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene. Embodiment 20: The method of embodiment 19, wherein the polypeptide comprises an antibody, an antigen binding fragment thereof, or a receptor that binds to the gene. Embodiment 21: The method of embodiment 20, wherein the antibody is an IgG, IgA, IgM, IgE or IgD, or a subclass thereof. Embodiment 22: The method of embodiment 21, wherein the IgG is an IgG1, IgG2, IgG3 or IgG4. Embodiment 23: The method of any one of embodiments 20 to 22 wherein the antigen binding fragment is a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH. -106- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Embodiment 24: The method of any one of embodiments 11 to 23, wherein the agent is contacted with the sample in conditions under which it can bind to the one or more targets. Embodiment 25: The method of any one of embodiments 11 to 24, wherein the method comprises detection of an antibody-protein product by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting. Embodiment 26: The method of any one of embodiments 11 to 25, wherein the sample comprises cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample. Embodiment 27: The method of any one of embodiments 1 to 26, wherein the autoimmune disease or fibrotic disease comprises polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, relapsing polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatica, Spondyloarthritides, pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, drug-resistant rheumatoid arthritis, neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enteropathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing -107- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, irritable bowel syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dyslipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility. -108- 4905-6836-1039.1 Atty. Dkt. No.: 116639-3110 Embodiment 28: The method of any one of embodiments 1 to 27, wherein the autoimmune disease or fibrotic disease comprises ulcerative colitis, Crohn's disease, or rheumatoid arthritis. Embodiment 29: The method of any one of embodiments 1-28, wherein the one or more targets are selected from: TIAM1, IGFBP4, IL21, IL21-R, PASK, TMEM155, HMOX1, CD81, CAV1, FCRL3, PGM2L1, and ICA1. Other aspects are set forth within the following claims. -109- 4905-6836-1039.1

Claims

Atty. Dkt. No.: 116639-3110 WHAT IS CLAIMED IS:

1. A method of treating an autoimmune disease or a fibrotic disease in a subject comprising administering to the subject an effective amount of an agent to modulate the activity of a population of T-cells expressing one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject.

2. A method of treating an autoimmune disease or fibrotic disease in a subject comprising administering to the subject an effective amount of an agent that modulates expression in T cells of one or more of the targets identified herein, thereby treating the autoimmune disease or fibrotic disease in the subject.

3. The method of claim 1 or claim 2, wherein the T-cells are CD4+ or CD8+ T-cells.

4. The method of any one of claims 1-3, wherein the agent is selected from a small molecule, an antibody, lentivirus, adeno-associated virus, an antisense oligonucleotide, an siRNA or an miRNA.

5. The method of claim 4, wherein the siRNA or miRNA is complementary to at least a fragment of a polynucleotide encoding one or more of the targets identified herein.

6. The method of any one of claims 2 to 5, wherein administration of the agent induces higher or lower than baseline expression of the one or more of the targets in T-cells.

7. The method of claim 6, wherein higher than baseline expression is at least about a 2-fold increase in expression of the one or more genes relative to baseline expression and / or lower than baseline expression is at least about a 2-fold decrease in expression of the one or more genes relative to baseline expression.

8. The method of claim 6 or claim 7, wherein baseline expression comprises normalized mean gene expression.

9. The method of any one of claims 1 to 8, further comprising administering to the subject an additional therapy for the autoimmune disease or the fibrotic disease. -110- 4905-6836-1039.1Atty. Dkt. No.: 116639-3110 10. The method of claim 9, wherein the additional therapy comprises one or more monoclonal antibodies for the treatment of the autoimmune or the fibrotic disease.

11. A method of diagnosing an autoimmune disease or fibrotic disease in a subject, comprising contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample isolated from the subject, wherein the presence of the one or more genes at higher or lower than baseline expression levels is a diagnostic indicator of the autoimmune or the fibrotic disease or wherein the absence of the one or more genes at higher or lower than baseline expression levels is not diagnostic indicator of the autoimmune disease or fibrotic disease.

12. A method of identifying a subject that will or is likely to respond to one or more of an autoimmune therapy or a fibrotic disease therapy, comprising contacting a sample isolated from the subject with an agent that detects the presence of one or more of the targets identified herein in the sample, wherein the presence of the one or more genes at higher or lower than baseline expression levels indicates that the subject is likely to respond to the one or more of the autoimmune therapy or the fibrotic disease therapy.

13. The method of claim 12, wherein baseline expression is normalized mean gene expression.

14. The method of claim 13, wherein higher than baseline expression of the one or more genes is at least about a 2-fold increase in expression relative to baseline expression and / or lower than baseline expression of the one or more genes is at least about a 2-fold decrease in expression relative to baseline expression.

15. The method of any one of claims 11-14, further comprising administering to a patient in need thereof an autoimmune therapy or a fibrotic disease therapy to the subject.

16. The method of claim 15, wherein the autoimmune therapy or the fibrotic disease therapy is one or more of hormonal therapy, immunotherapy, or monoclonal antibody therapy.

17. The method of any one of claims 11 to 16, wherein sample is contacted with an agent, optionally including a detectable label or tag. -111- 4905-6836-1039.1Atty. Dkt. No.: 116639-3110 18. The method of claim 17, wherein the detectable label or tag comprises a radioisotope, a metal, horseradish peroxidase, alkaline phosphatase, avidin or biotin.

19. The method of claim 17 or 18, wherein the agent comprises a polypeptide that binds to an expression product encoded by the gene, or a polynucleotide that hybridizes to a nucleic acid sequence encoding all or a portion of the gene.

20. The method of claim 19, wherein the polypeptide comprises an antibody, an antigen binding fragment thereof, or a receptor that binds to the gene.

21. The method of claim 20, wherein the antibody is an IgG, IgA, IgM, IgE or IgD, or a subclass thereof.

22. The method of claim 21, wherein the IgG is an IgG1, IgG2, IgG3 or IgG4.

23. The method of any one of claims 20 to 22 wherein the antigen binding fragment is a Fab, Fab’, F(ab’)2, Fv, Fd, single-chain Fvs (scFv), disulfide-linked Fvs (sdFv) or VL or VH.

24. The method of any one of claims 11 to 23, wherein the agent is contacted with the sample in conditions under which it can bind to the one or more targets.

25. The method of any one of claims 11 to 24, wherein the method comprises detection of an antibody-protein product by immunohistochemistry (IHC), in-situ hybridization (ISH), ELISA, immunoprecipitation, immunofluorescence, chemiluminescence, radioactivity, X-ray, nucleic acid hybridization, protein-protein interaction, immunoprecipitation, flow cytometry, Western blotting, polymerase chain reaction, DNA transcription, Northern blotting and / or Southern blotting.

26. The method of any one of claims 11 to 25, wherein the sample comprises cells, tissue, an organ biopsy, an epithelial tissue, a lung, respiratory or airway tissue or organ, a circulatory tissue or organ, a skin tissue, bone tissue, muscle tissue, head, neck, brain, skin, bone and / or blood sample.

27. The method of any one of claims 1 to 26, wherein the autoimmune disease or fibrotic disease comprises polymyositis, vasculitis syndrome, giant cell arteritis, Takayasu arteritis, -112- 4905-6836-1039.1Atty. Dkt. No.: 116639-3110 relapsing, polychondritis, acquired hemophilia A, Still's disease, adult-onset Still's disease, amyloid A amyloidosis, polymyalgia rheumatic, Spondyloarthritides, Pulmonary arterial hypertension, graft-versus-host disease, autoimmune myocarditis, contact hypersensitivity (contact dermatitis), gastro-esophageal reflux disease, erythroderma, Behcet's disease, amyotrophic lateral sclerosis, transplantation, rheumatoid arthritis, juvenile rheumatoid arthritis, malignant rheumatoid arthritis, Drug-Resistant Rheumatoid Arthritis, Neuromyelitis optica, Kawasaki disease, polyarticular or systemic juvenile idiopathic arthritis, psoriasis, nonalcoholic fatty liver disease, primary biliary cholangitis, autoimmune hepatitis, autoimmune kidney disease, chronic obstructive pulmonary disease (COPD), Castleman’s disease, asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic asthma (mild intermittent, mild persistent, moderate persistent, or severe persistent), allergic encephalomyelitis, arthritis, arthritis chronica progrediente, reactive arthritis, psoriatic arthritis, enterophathic arthritis, arthritis deformans, rheumatic diseases, spondyloarthropathies, ankylosing spondylitis, Reiter syndrome, hypersensitivity (including both airway hypersensitivity and dermal hypersensitivity), allergies, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, erythema nodosum leprosum, Sjögren’s Syndrome, inflammatory muscle disorders, polychondritis, Wegener's granulomatosis, dermatomyositis, Steven-Johnson syndrome, chronic active hepatitis, myasthenia gravis, idiopathic sprue, autoimmune inflammatory bowel disease, ulcerative colitis, Crohn's disease, Irritable Bowel Syndrome, endocrine ophthalmopathy, scleroderma, Grave’s disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, vaginitis, proctitis, insulin-dependent diabetes mellitus, insulin-resistant diabetes mellitus, juvenile diabetes (diabetes mellitus type I), autoimmune haematological disorders, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia (ITP), autoimmune uveitis, uveitis (anterior and posterior), keratoconjunctivitis sicca, vernal keratoconjunctivitis, interstitial lung fibrosis, glomerulonephritis (with and without nephrotic syndrome), idiopathic nephrotic syndrome or minimal change nephropathy, inflammatory disease of skin, cornea inflammation, myositis, loosening of bone implants, metabolic disorder, atherosclerosis, dislipidemia, bone loss, osteoarthritis, osteoporosis, periodontal disease of obstructive or inflammatory airways diseases, -113- 4905-6836-1039.1Atty. Dkt. No.: 116639-3110 bronchitis, pneumoconiosis, pulmonary emphysema, acute and hyperacute inflammatory reactions, acute infections, septic shock, endotoxic shock, adult respiratory distress syndrome, meningitis, pneumonia, cachexia wasting syndrome, stroke, herpetic stromal keratitis, dry eye disease, iritis, conjunctivitis, keratoconjunctivitis, Guillain-Barre syndrome, Stiff-man syndrome, Hashimoto's thyroiditis, autoimmune thyroiditis, encephalomyelitis, acute rheumatic fever, sympathetic ophthalmia, Goodpasture’s syndrome, systemic necrotizing vasculitis, antiphospholipid syndrome, Addison's disease, pemphigus vulgaris, pemphigus foliaceus, dermatitis herpetiformis, atopic dermatitis, eczematous dermatitis, aphthous ulcer, lichen planus, autoimmune alopecia, Vitiligo, autoimmune hemolytic anemia, autoimmune thrombocytopenic purpura, pernicious anemia, sensorineural hearing loss, idiopathic bilateral progressive sensorineural hearing loss, autoimmune polyglandular syndrome type I or type II, immune infertility and immune-mediated infertility.

28. The method of any one of claims 1 to 27, wherein the autoimmune disease or fibrotic disease comprises ulcerative colitis, Crohn's disease, or rheumatoid arthritis.

29. The method of any one of claims 1-28, wherein the one or more targets are selected from: TIAM1, IGFBP4, IL21, IL21-R, PASK, TMEM155, HMOX1, CD81, CAV1, FCRL3, PGM2L1, and ICA1. -114- 4905-6836-1039.1

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