Synthetic cytokine receptors

Abstract

Provided herein are synthetic cytokine receptors, wherein each synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain. Also provided herein are engineered cells expressing one or more such synthetic cytokine receptors.

Description

30761-20002.40 SYNTHETIC CYTOKINE RECEPTORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No.63 / 510,921 filed on June 29, 2023, entitled “SYNTHETIC CYTOKINE RECEPTORS”, U.S. Provisional Patent Application No.63 / 615,248 filed on December 27, 2023, entitled “SYNTHETIC CYTOKINE RECEPTORS”, and U.S. Provisional Patent Application No.63 / 555,875 filed on February 20, 2024, entitled “SYNTHETIC CYTOKINE RECEPTORS”, the contents of which are incorporated by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 30761-2000240.XML created June 28, 2024, which is 277,183 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety. FIELD

[0003] The present disclosure generally relates to synthetic cytokine receptors and engineered cells expressing one or more such synthetic cytokine receptors. BACKGROUND

[0004] Therapies that use adoptively transferred genetically engineered T cells have shown substantial anti-tumor activity in patients with hematopoietic malignancies. However, such therapies have limited benefit in patients with solid tumors. One major limitation is the poor in vivo expansion and persistence of adoptively transferred T cells. To circumvent this limitation, patients have been lymphodepleted with chemotherapy and / or radiation prior to being transferred with engineered T cells. However, some patients are too weak to receive toxic regimens such as chemotherapy and radiation. The other major limitation is that the T cells that do successfully expand and persist in vivo become terminally differentiated and dysfunctional. Thus, improved systems and engineered cells are needed to address these problems. Provided embodiments address these needs. SUMMARY

[0005] The present disclosure provides synthetic cytokine receptors, engineered cells expressing one or more such synthetic cytokine receptors, and uses thereof.30761-20002.40

[0006] In some embodiments, provided herein is a synthetic cytokine receptor, comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0007] In some embodiments, provided herein is a polynucleotide encoding a synthetic cytokine receptor, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0008] In some embodiments, provided herein is a vector comprising a polynucleotide encoding a synthetic cytokine receptor, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0009] In some embodiments, provided herein is a method of engineering an isolated cell, comprising contacting the cell with a polynucleotide encoding a synthetic cytokine receptor or a vector comprising such a polynucleotide, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0010] In some embodiments, provided herein is an engineered cell expressing one or more synthetic cytokine receptors, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0011] In some embodiments, provided herein is a population of cells, comprising at least one engineered cell expressing one or more synthetic cytokine receptors, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0012] In some embodiments, provided herein is a pharmaceutical composition comprising an engineered cell expressing one or more synthetic cytokine receptors or a population of cells comprising at least one such engineered cell, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain.

[0013] In some embodiments, provided herein is a method of treating a cancer in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0014] In some aspects, provided herein is a synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an intracellular domain capable of interleukin 9 receptor (IL-9R) signaling.

[0015] In some embodiments, the intracellular domain capable of IL-9R signaling comprises an IL-9R intracellular domain or a variant thereof. In some embodiments, the intracellular domain capable of IL-9R signaling comprises a chimeric JAK / STAT fusion domain.

[0016] In some aspects, provided herein is a synthetic cytokine receptor, comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular30761-20002.40 domain or variant thereof, wherein the synthetic cytokine receptor is a constitutively active cytokine receptor.

[0017] In some embodiments, the synthetic cytokine receptor is a multimer. In some embodiments, the synthetic cytokine receptor is a multimer of identical polypeptide chains each comprising the extracellular domain, the transmembrane domain and the IL-9R intracellular domain or variant thereof. In some embodiments, the multimer is a dimer. In some embodiments, the dimer is a homodimer. In some embodiments, each polypeptide chain is constitutively multimerized.

[0018] In some embodiments, the synthetic cytokine receptor comprises at least one self- assembly domain. In some embodiments, the at least one self-assembly domain is the extracellular domain and / or the transmembrane domain.

[0019] In some embodiments, the synthetic cytokine receptor is multimerized through the transmembrane domain and / or the extracellular domain. In some embodiments, the synthetic cytokine receptor is multimerized through the transmembrane domain and the extracellular domain.

[0020] In some aspects, provided herein is a synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or a variant thereof.

[0021] In some embodiments, the extracellular domain and / or the transmembrane domain are heterologous to the IL-9R. In some embodiments, the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from the same protein. In some embodiments, the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from different proteins.

[0022] In some embodiments, the transmembrane domain is 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 amino acids in length. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA) Carnitine palmitoyltransferase 1 (CPT1), a tumor necrosis factor receptor (TNFR) or Muc24. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Thrombopoietin receptor.

[0023] In some embodiments, the transmembrane domain promotes alpha-helix dimerization. In some embodiments, the transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68). In some embodiments, the transmembrane domain comprises the motif LIxxGVxxGVxxT (SEQ ID NO: 70).

[0024] In some embodiments, the transmembrane domain is a transmembrane domain derived from Glycophorin A (GpA) or a variant thereof that comprises one or more mutations (e.g, 1, 2, 3, 4, 5 or 6 mutations) compared to a wild-type GpA transmembrane domain, wherein the variant GpA is sufficient to promote alpha-helix dimerization. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA). In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ30761-20002.40 ID NO: 22 or SEQ ID NO:43. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 43.

[0025] In some embodiments, the transmembrane domain comprises GXXXG (SEQ ID NO: 68) and GXXXA (SEQ ID NO: 69) motifs. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Carnitine palmitoyltransferase 1 (CPT1). In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 45. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 45.

[0026] In some embodiments, the synthetic cytokine receptor comprises the motif AXXXA (SEQ ID NO:77) or AXXXS (SEQ ID NO: 78). In some embodiments, the synthetic cytokine receptor comprises the motif ĭPXĭ (SEQ ID NO:75) or ĭTXXAĭ (SEQ ID NO: 76). In some embodiments, the transmembrane domain is derived from a TNFR. In some embodiments, the TNFR is TACI, DR5, p75NTR, Fas, TNFR1, TNFR2 or OX40.

[0027] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from DR5. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 46. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 46.

[0028] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from TACI. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 44. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 44.

[0029] In some embodiments, the transmembrane domain comprises 1 to 6 cysteine residues. In some embodiments, the transmembrane domain promotes disulfide-linked dimerization. In some embodiments, the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

[0030] In some embodiments, the transmembrane domain is a variant transmembrane domain that comprises one or more mutations compared to a wild-type transmembrane domain to promote homodimerization of the receptor polypeptide.

[0031] In some embodiments, the one or more mutations promote alpha-helix dimerization or disulfide-linked dimerization. In some embodiments, the one or more mutations introduces at least one cysteine into the transmembrane domain. In some embodiments, the one or more mutations introduces a proline into the transmembrane domain. In some embodiments, the one or more mutations introduces a threonine into the transmembrane domain.

[0032] In some embodiments, the one or more mutations introduces a trimer peptide of cysteine, proline, and another amino acid other than cysteine or proline into the transmembrane domain. In some embodiments, the one or more mutations introduces a trimer peptide of cysteine, proline, threonine (CPT or TCP) into the transmembrane domain.30761-20002.40

[0033] In some embodiments, the transmembrane domain is a variant IL-7R transmembrane domain and the one or more mutations is in the wild-type transmembrane sequence PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 71). In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 6, SEQ ID NO:7 or SEQ ID NO: 21. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO:21.

[0034] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Muc24. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 23. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 23.

[0035] In some embodiments, the extracellular domain is between about 150 to 260 amino acids in length.

[0036] In some embodiments, the extracellular domain is a dimerizing domain. In some embodiments, the dimerizing domain comprises a hinge region. In some embodiments, the extracellular domain promotes disulfide-linked dimerization. In some embodiments, the extracellular domain comprises 1 to 6 cysteine residues. In some embodiments, the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

[0037] In some embodiments, the extracellular domain is derived from the extracellular domain of CD34, DAP12, Glycophorin A, CD8, or Muc24. In some embodiments, the extracellular domain comprises an extracellular domain derived from Thrombopoietin receptor.

[0038] In some embodiments, the extracellular domain comprises an extracellular domain of CD8 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 18 or SEQ ID NO: 19. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 19.

[0039] In some embodiments, the extracellular domain comprises an extracellular domain of CD34 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 4. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 4.

[0040] In some embodiments, the extracellular domain is an extracellular domain of Muc24 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 20. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 20.

[0041] In some embodiments, the extracellular domain is an extracellular domain of DAP12 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the30761-20002.40 extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 5. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 5.

[0042] In some embodiments, the extracellular domain is an extracellular domain of Glycophorin A (GpA) or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 16 or SEQ ID NO: 17. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 16 or SEQ ID NO: 17.

[0043] In some embodiments, the IL-9R intracellular domain or variant thereof is about 100 to 260 amino acids in length. In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX1 motif and / or a BOX2 motif. In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX2 motif. In some embodiments, the IL-9R intracellular domain or variant thereof is 230 amino acids in length.

[0044] In some embodiments, the IL-9R intracellular domain is wild-type IL-9R intracellular domain or a variant thereof that comprises one or more mutations compared to the wild-type IL-9R intracellular domain set forth in SEQ ID NO: 8. In some embodiments, the one or more mutations comprises one or more amino acid insertions, deletions, and / or substitutions. In some embodiments, the one or more mutations promote signaling through STAT1, STAT3, and / or STAT5 pathways. In some embodiments, the IL-9R intracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 8.

[0045] In some embodiments, the IL-9R intracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56.

[0046] In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO: 67. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO: 67.30761-20002.40

[0047] In some embodiments, the IL-9R intracellular domain or variant thereof comprises one or more amino acid deletions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).

[0048] In some embodiments, the IL-9R intracellular domain or variant thereof is a truncated IL- 9R that lacks a contiguous sequence of amino acids at the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the truncated IL-9R intracellular domain or variant thereof is truncated by between 62 and 99 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the IL-9R intracellular domain or variant thereof is a truncated IL-9R that lacks amino acids 132 to 230 of SEQ ID NO:8 or lacks amino acids 134 to 230 of SEQ ID NO:8.

[0049] In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO: 104. In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO: 104.

[0050] In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 63. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 63.

[0051] In some embodiments, the IL-9R intracellular domain or variant thereof comprises one or more amino acid substitutions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).

[0052] In some embodiments, the IL-9R intracellular domain or variant thereof comprises a STAT binding motif or a variant thereof. In some embodiments, the STAT binding motif comprises a STAT1, STAT3, and / or STAT5 binding motif. In some embodiments, the STAT binding motif comprises YLPQ (SEQ ID NO: 171). In some embodiments, the STAT binding motif comprises a variant STAT binding motif. In some embodiments, the variant STAT binding motif comprises YRPQ (SEQ ID NO: 172). In some embodiments, the variant STAT binding motif comprises YLPL (SEQ ID NO: 173). In some embodiments, the variant STAT binding motif comprises YLKQ (SEQ ID NO: 174).

[0053] In some embodiments, the variant IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO: 109. In some embodiments, the variant IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO: 109. In some embodiments, the chimeric JAK / STAT fusion domain comprises a JAK binding domain from a type I cytokine receptor and a STAT binding domain from an IL-9R intracellular domain.

[0054] In some embodiments, the IL-9R STAT binding domain comprises amino acid residues 73 to 230 of SEQ ID NO: 8. In some embodiments, the STAT binding domain is 59 to 158 amino30761-20002.40 acids in length and comprises an IL-9R STAT binding motif. In some embodiments, the IL-9R STAT binding motif comprises YLPQ (SEQ ID NO: 171). In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the N-terminus of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the C- terminus of SEQ ID NO: 8.

[0055] In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 1 to 72 and / or 132 to 230 of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 122 or SEQ ID NO: 123. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence of SEQ ID NO: 122 or SEQ ID NO: 123.

[0056] In some embodiments, the type I cytokine receptor is selected from the group consisting of interleukin 2 receptor (IL-2R), interleukin 4 receptor (IL-4R), interleukin 7 receptor (IL-7R), interleukin 13 receptor (IL-13R), interleukin 15 receptor (IL-15R), and interleukin 2 receptor (IL- 21R). In some embodiments, the type I cytokine receptor is IL-7R. In some embodiments, the IL-7R JAK binding domain is 65 amino acids in length and comprises a box 1 motif. In some embodiments, the IL-7R JAK binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 121. In some embodiments, the IL-7R JAK binding domain comprises an amino acid sequence of SEQ ID NO: 121.

[0057] In some embodiments, the chimeric JAK / STAT fusion domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 114 or SEQ ID NO: 116. In some embodiments, the chimeric JAK / STAT fusion domain comprises an amino acid sequence of SEQ ID NO: 114 or SEQ ID NO: 116.

[0058] In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO: 117. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO: 117.

[0059] In some embodiments, the synthetic cytokine receptor is a constitutively active cytokine receptor. In some embodiments, the synthetic cytokine receptor elicits signaling through STAT1, STAT3, and / or STAT5 pathways. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 is increased compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 is sustained for a longer period of time compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R. In some embodiments, sustained STAT1, STAT3, and / or STAT5 signaling is determined by phosphorylation status of STAT1, STAT3, and / or STAT5.In some aspects, provided herein is a polynucleotide encoding any of the synthetic cytokine receptors provided herein.30761-20002.40

[0060] In some aspects, provided herein is a vector, comprising any one of the polynucleotides provided herein.

[0061] In some aspects, provided herein is a method of engineering an isolated cell, comprising contacting the cell with any one of the polynucleotides or any one of the vectors provided herein. In some aspects, provided herein is an engineered cell expressing any one of the synthetic cytokine receptors provided herein.

[0062] In some aspects, provided herein is a synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an intracellular domain capable of interleukin 9 receptor (IL-9R) signaling. In some embodiments, the intracellular domain capable of IL-9R signaling comprises an IL-9R intracellular domain or a variant thereof. In some embodiments, the intracellular domain capable of IL-9R signaling comprises a chimeric JAK / STAT fusion domain.

[0063] In some aspects, provided herein is an engineered cell expressing a synthetic cytokine receptor, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or a variant thereof, wherein the synthetic cytokine receptor is a constitutively active cytokine receptor.

[0064] In some embodiments, the synthetic cytokine receptor is a multimer. In some embodiments, the synthetic cytokine receptor is a multimer of identical polypeptide chains each comprising the extracellular domain, the transmembrane domain and the IL-9R intracellular domain or a variant thereof. In some embodiments, the multimer is a dimer. In some embodiments, the dimer is a homodimer. In some embodiments, each polypeptide chain is constitutively multimerized.

[0065] In some embodiments, the synthetic cytokine receptor comprises at least one self- assembly domain. In some embodiments, the at least one self-assembly domain is the extracellular domain and / or the transmembrane domain. In some embodiments, the synthetic cytokine receptor is multimerized through the transmembrane domain and / or the extracellular domain.

[0066] In some embodiments, the synthetic cytokine receptor is multimerized through the transmembrane domain and the extracellular domain.

[0067] In some aspects, provided herein is an engineered cell expressing a synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or variant thereof. In some embodiments, the extracellular domain and / or the transmembrane domain are heterologous to the IL-9R. In some embodiments, the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from the same protein. In some embodiments, the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from different proteins.

[0068] In some embodiments, the transmembrane domain is 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 amino acids in length. In some embodiments, the transmembrane domain comprises30761-20002.40 a transmembrane domain derived from Glycophorin A (GpA) Carnitine palmitoyltransferase 1 (CPT1), a tumor necrosis factor receptor (TNFR) or Muc24. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Thrombopoietin receptor.

[0069] In some embodiments, the transmembrane domain promotes alpha-helix dimerization. In some embodiments, the transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68). In some embodiments, the transmembrane domain comprises the motif LIxxGVxxGVxxT (SEQ ID NO: 70).

[0070] In some embodiments, the transmembrane domain is a transmembrane domain derived from Glycophorin A (GpA) or a variant thereof that comprises one or more mutations (e.g, 1, 2, 3, 4, 5 or 6 mutations) compared to a wild-type GpA transmembrane domain, wherein the variant GpA is sufficient to promote alpha-helix dimerization. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA).

[0071] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 22 or SEQ ID NO:43. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 43.

[0072] In some embodiments, the transmembrane domain comprises GXXXG (SEQ ID NO: 68) and GXXXA (SEQ ID NO: 69) motifs. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Carnitine palmitoyltransferase 1 (CPT1). In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 45. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 45.

[0073] In some embodiments, the synthetic cytokine receptor comprises the motif AXXXA (SEQ ID NO:77) or AXXXS (SEQ ID NO: 78). In some embodiments, the synthetic cytokine receptor comprises the motif ĭPXĭ (SEQ ID NO:75) or ĭTXXAĭ (SEQ ID NO: 76). In some embodiments, the transmembrane domain is derived from a TNFR. In some embodiments, the TNFR is TACI, DR5, p75NTR, Fas, TNFR1, TNFR2 or OX40.

[0074] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from DR5. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 46. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 46.

[0075] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from TACI. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 44. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 44.

[0076] In some embodiments, the transmembrane domain comprises 1 to 6 cysteine residues. In some embodiments, the transmembrane domain promotes disulfide-linked dimerization. In some30761-20002.40 embodiments, the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

[0077] In some embodiments, the transmembrane domain is a variant transmembrane domain that comprises one or more mutations compared to a wild-type transmembrane domain to promote homodimerization of the receptor polypeptide. In some embodiments, the one or more mutations promote alpha-helix dimerization or disulfide-linked dimerization.

[0078] In some embodiments, the one or more mutations introduces at least one cysteine into the transmembrane domain. In some embodiments, the one or more mutations introduces a proline into the transmembrane domain. In some embodiments, the one or more mutations introduces a threonine into the transmembrane domain. In some embodiments, the one or more mutations introduces a trimer peptide of cysteine, proline, and another amino acid other than cysteine or proline into the transmembrane domain. In some embodiments, the one or more mutations introduces a trimer peptide of cysteine, proline, threonine (CPT or TCP) into the transmembrane domain.

[0079] In some embodiments, the transmembrane domain is a variant IL-7R transmembrane domain and the one or more mutations is in the wild-type transmembrane sequence PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 71).

[0080] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 6, SEQ ID NO:7 or SEQ ID NO: 21. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO:21.

[0081] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Muc24. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 23. In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 23.

[0082] In some embodiments, the extracellular domain is between about 150 to 260 amino acids in length. In some embodiments, the extracellular domain is a dimerizing domain. In some embodiments, the dimerizing domain comprises a hinge region. In some embodiments, the extracellular domain promotes disulfide-linked dimerization. In some embodiments, the extracellular domain comprises 1 to 6 cysteine residues. In some embodiments, the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

[0083] In some embodiments, the extracellular domain is derived from the extracellular domain of CD34, DAP12, Glycophorin A, CD8, or Muc24. In some embodiments, the extracellular domain comprises an extracellular domain derived from Thrombopoietin receptor.

[0084] In some embodiments, the extracellular domain comprises an extracellular domain of CD8 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ30761-20002.40 ID NO: 18 or SEQ ID NO: 19. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 19.

[0085] In some embodiments, the extracellular domain comprises an extracellular domain of CD34 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 4. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 4.

[0086] In some embodiments, the extracellular domain is an extracellular domain of Muc24 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 20. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, the extracellular domain is an extracellular domain of DAP12 or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 5. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 5.

[0087] In some embodiments, the extracellular domain is an extracellular domain of Glycophorin A (GpA) or a truncated portion thereof comprising at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 16 or SEQ ID NO: 17. In some embodiments, the extracellular domain comprises the amino acid sequence of SEQ ID NO: 16 or SEQ ID NO: 17.

[0088] In some embodiments, the IL-9R intracellular domain or variant thereof is about 100 to 260 amino acids in length. In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX1 motif and / or a BOX2 motif. In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX2 motif. In some embodiments, the IL-9R intracellular domain or variant thereof is 230 amino acids in length.

[0089] In some embodiments, the IL-9R intracellular domain is wild-type IL-9R intracellular domain or a variant thereof that comprises one or more mutations compared to the wild-type IL-9R intracellular domain set forth in SEQ ID NO: 8.

[0090] In some embodiments, the one or more mutations comprises one or more amino acid insertions, deletions, and / or substitutions. In some embodiments, the one or more mutations promote signaling through STAT1, STAT3, and / or STAT5 pathways.

[0091] In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 8.

[0092] In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID30761-20002.40 NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO: 56.

[0093] In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO: 67. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO: 67.

[0094] In some embodiments, the IL-9R intracellular domain or variant thereof comprises one or more amino acid deletions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8). In some embodiments, the IL-9R intracellular domain or variant thereof is a truncated IL-9R that lacks a contiguous sequence of amino acids at the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the truncated IL-9R intracellular domain or variant thereof is truncated by between 62 and 99 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain.

[0095] In some embodiments, the IL-9R intracellular domain or variant thereof is a truncated IL- 9R that lacks amino acids 132 to 230 of SEQ ID NO:8 or lacks amino acids 134 to 230 of SEQ ID NO:8.

[0096] In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO: 104. In some embodiments, the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO: 104.

[0097] In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 63. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 63.

[0098] In some embodiments, the IL-9R intracellular domain or variant thereof comprises one or more amino acid substitutions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).30761-20002.40

[0099] In some embodiments, the IL-9R intracellular domain or variant thereof comprises a STAT binding motif or a variant thereof. In some embodiments, the STAT binding motif comprises a STAT1, STAT3, and / or STAT5 binding motif. In some embodiments, the STAT binding motif comprises YLPQ (SEQ ID NO: 171). In some embodiments, the STAT binding motif comprises a variant STAT binding motif. In some embodiments, the variant STAT binding motif comprises YRPQ (SEQ ID NO: 172). In some embodiments, the variant STAT binding motif comprises YLPL (SEQ ID NO: 173). In some embodiments, the variant STAT binding motif comprises YLKQ (SEQ ID NO: 174). In some embodiments, the variant IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO: 109.

[0100] In some embodiments, the variant IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO: 109.

[0101] In some embodiments, the chimeric JAK / STAT fusion domain comprises a JAK binding domain from a type I cytokine receptor and a STAT binding domain from an IL-9R intracellular domain.

[0102] In some embodiments, the IL-9R STAT binding domain comprises amino acid residues 73 to 230 of SEQ ID NO: 8.

[0103] In some embodiments, the STAT binding domain is 59 to 158 amino acids in length and comprises an IL-9R STAT binding motif. In some embodiments, the IL-9R STAT binding motif comprises YLPQ (SEQ ID NO: 171). In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the N- terminus of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL- 9R STAT binding domain that lacks a contiguous sequence of amino acids at the C-terminus of SEQ ID NO: 8.

[0104] In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 1 to 72 and / or 132 to 230 of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 122 or SEQ ID NO: 123. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence of SEQ ID NO: 122 or SEQ ID NO: 123.

[0105] In some embodiments, the type I cytokine receptor is selected from the group consisting of interleukin 2 receptor (IL-2R), interleukin 4 receptor (IL-4R), interleukin 7 receptor (IL-7R), interleukin 13 receptor (IL-13R), interleukin 15 receptor (IL-15R), and interleukin 2 receptor (IL- 21R). In some embodiments, the type I cytokine receptor is IL-7R.

[0106] In some embodiments, the IL-7R JAK binding domain is 65 amino acids in length and comprises a box 1 motif. In some embodiments, the IL-7R JAK binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 121. In some embodiments, the IL- 7R JAK binding domain comprises an amino acid sequence of SEQ ID NO: 121. In some30761-20002.40 embodiments, the chimeric JAK / STAT fusion domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 114 or SEQ ID NO: 116. In some embodiments, the chimeric JAK / STAT fusion domain comprises an amino acid sequence of SEQ ID NO: 114 or SEQ ID NO: 116.

[0107] In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO: 117. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO: 117.

[0108] In some embodiments, the synthetic cytokine receptor is a constitutively active cytokine receptor.

[0109] In some embodiments, the synthetic cytokine receptor elicits signaling through STAT1, STAT3, and / or STAT5 pathways. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 is increased compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 is sustained for a longer period of time compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R. In some embodiments, sustained STAT1, STAT3, and / or STAT5 signaling is determined by phosphorylation status of STAT1, STAT3, and / or STAT5.

[0110] In some embodiments, the engineered cell further expresses at least one different type of engineered receptor. In some embodiments, the at least one different type of engineered receptor is a chimeric antigen receptor. In some embodiments, the extracellular domain of the chimeric antigen receptor binds to an antigen expressed on a cancer cell. In some embodiments, the extracellular domain of the chimeric antigen receptor binds to an idiotype of an antibody. In some embodiments, the antibody is against an antigen expressed on a cancer cell. In some embodiments, the cancer cell is a blood cancer cell or a solid tumor cancer cell.

[0111] In some embodiments, the cell is an immune cell. In some embodiments, the cell is a lymphocyte. In some embodiments, the engineered cell is an immune effector cell. In some embodiments, the cell is a T cell or a Natural Killer (NK) cell. In some embodiments, the cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell. In some embodiments, the immune effector cell is a cytotoxic T cell. In some embodiments, the immune effector cell is a natural killer cell. In some embodiments, the cell is a primary cell. In some embodiments, the cell is a human cell. In some aspects, provided herein is a population of cells, comprising at least one of any of the engineered cells provided herein. In some embodiments, the at least one engineered cell comprises engineered CD4+ T cells and engineered CD8+ T cells.

[0112] In some aspects, provided herein is a pharmaceutical composition comprising any of the engineered cells provided herein or any of the populations of cells provided herein. In some embodiments, the pharmaceutical composition further comprises a pharmaceutical acceptable carrier.30761-20002.40 In some embodiments, the pharmaceutical composition further comprises a cryoprotectant. In some embodiments, the pharmaceutical composition is for use in treating a cancer in a subject.

[0113] In some aspects, provided herein is a method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of any of the pharmaceutical compositions provided herein. In some embodiments, the disease or condition is a cancer.

[0114] In some embodiments, the engineered cell of the pharmaceutical composition expresses an engineered antigen receptor that binds to an antigen expressed on a cell of the cancer. In some embodiments, the engineered antigen receptor is a chimeric antigen receptor. In some embodiments, the engineered antigen receptor is a T cell receptor.

[0115] In some aspects, provided herein is a method of improving function of an immune cell, comprising introducing to the immune cell any one of the polynucleotides or vectors provided herein, wherein improving immune cell function comprises increased STAT1, STAT3, and / or STAT5 signaling compared to an immune cell expressing wild-type IL-9R.

[0116] In some aspects, provided herein is a method of improving cytotoxicity of an immune cell, comprising introducing to the immune cell any one of the polynucleotides or vectors provided herein, wherein improving immune cell cytotoxicity comprises increased target cell killing compared to an immune cell expressing wild-type IL-9R.

[0117] In some aspects, provided herein is a method of improving viability of an immune cell, comprising introducing to the immune cell any one of the polynucleotides or vectors provided herein, wherein improving viability of the immune cell comprises decreased immune cell death compared to an immune cell expressing wild-type IL-9R.

[0118] In some aspects, provided herein is a method of improving cytokine secretion by an immune cell, comprising introducing to the immune cell any one of the polynucleotides or vectors provided herein, wherein improving cytokine secretion comprises increased secretion of interferon compared to an immune cell expressing wild-type IL-9R.

[0119] In some embodiments, the interferon comprises IFNȖ. In some embodiments, the immune cell further comprises an engineered antigen receptor. In some embodiments, the one different type of engineered receptor is a chimeric antigen receptor (CAR). In some embodiments, the extracellular domain of the CAR binds to an antigen expressed on a cancer cell. In some embodiments, the cancer cell is a blood cancer cell or a solid tumor cancer cell.

[0120] In some embodiments, the immune cell is a lymphocyte. In some embodiments, the immune cell is an effector cell. In some embodiments, the immune cell is a T cell or NK cell. In some embodiments, the immune cell is a T cell. In some embodiments, the immune cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell. In some embodiments, the immune cell is a cytotoxic T cell. In some embodiments, the immune cell is a NK cell. In some embodiments, the immune cell is a primary cell.30761-20002.40

[0121] In some embodiments, provided herein is a method of improving function of an immune cell, comprising introducing to the immune cell any of the polynucleotides or vectors provided herein, thereby improving function of the immune cell.

[0122] In some embodiments, improving immune cell function comprises one or more of increased STAT signaling, increased cytotoxicity, increased proliferation, increased viability, increased cytokine secretion, and increased cytotoxic protein secretion compared to a reference cell.

[0123] In some embodiments, the reference cell comprises a non-engineered immune cell or an engineered immune cell. In some embodiments, the engineered immune cell expresses an engineered antigen receptor. In some embodiments, the engineered antigen receptor is a wild-type IL-9R, a chimeric antigen receptor (CAR) or a T cell receptor (TCR).

[0124] In some embodiments, increased STAT signaling comprises increased STAT1, STAT3 and / or STAT5 signaling. In some embodiments, increased cytotoxicity comprises increased killing of a target cell. In some embodiments, increased cytokine secretion comprises increased secretion of one or more of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), and TNFĮ. In some embodiments, increased cytotoxic protein secretion comprises increased secretion of one or more of granzyme A, granzyme B, granulysin and perforin. In some embodiments, increased viability comprises decreased cell death.

[0125] In some embodiments, the immune cell is a lymphocyte. In some embodiments, the immune cell is an effector cell. In some embodiments, the immune cell is a T cell or NK cell. In some embodiments, the immune cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell. In some embodiments, the immune cell is a cytotoxic T cell. In some embodiments, the immune cell is a NK cell. In some embodiments, the immune cell is a primary cell. BRIEF DESCRIPTION OF THE FIGURES

[0126] FIG.1 shows the design of exemplary synthetic cytokine receptors.

[0127] FIG.2 shows the expression of exemplary synthetic cytokine receptors on the surface of primary human CD3-positive T cells, including CD8+ T cells (left panel) or CD4+ T cells (right panel).

[0128] FIGS.3A and 3B show the surface expression level of CD27 and CD45RA 5 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing the 9RC synthetic cytokine receptor or in primary human CD3- positive T cells that were untransduced (“UTD”). FIG.3A is a representative flow cytometry dot plot with CD45RA staining on the x-axis and CD27 staining on the y-axis. FIG.3B depicts the percent of T cells that were positive for CD45RA and CD27 in UTD T cells or in 9RC+ transduced T cells.

[0129] FIG.4 shows the surface expression level of CD27 and CD45RA 12 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary30761-20002.40 synthetic cytokine receptor (9RC, 9RC2, or 9RD2) or in primary human CD3-positive T cells that were untransduced.

[0130] FIG.5 shows the surface expression level of CD27 and Fas 16 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary synthetic cytokine receptor (9RC, 9RC2, or 9RD2) or in primary human CD3-positive T cells that were untransduced.

[0131] FIG.6A shows the surface expression level of CD27 and Fas among all cells 16 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary synthetic cytokine receptor (9RC or 9RC2), the exemplary synthetic cytokine receptor 9RC co-expressed with a CAR separated by a 2A sequence (designated “40bbz-2a-CD34-9RC”), or in untransduced cells. FIG.6B shows the surface expression level of CD27 and Fas among Flag-positive cells 16 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary synthetic cytokine receptor (9RC or 9RC2) or the exemplary synthetic cytokine receptor 9RC co-expressed with a CAR separated by a 2A cleavable linker (designated “40bbz-2a-CD34-9RC”).

[0132] FIG.7A shows the surface expression level of CCR7 and CD45RA among all cells 16 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary synthetic cytokine receptor (9RC or 9RC2), the exemplary synthetic cytokine receptor 9RC co-expressed with a CAR separated by a 2A cleavable linker (designated “40bbz-2a-CD34- 9RC”), or in untransduced cells. FIG.7B shows the surface expression level of CCR7 and CD45RA among Flag-positive cells 16 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary synthetic cytokine receptor (9RC or 9RC2) or the exemplary synthetic cytokine receptor 9RC co-expressed with a CAR separated by a 2A cleavable linker (designated “40bbz-2a-CD34-9RC”).

[0133] FIG.8 shows the surface expression level of CD27 in 9RC expressing primary human CD3-positive T cells based on geometric mean fluorescence intensity (gMFI) as determined by flow cytometry.

[0134] FIGS.9A-9B show the surface expression level of CD57 in 9RC expressing primary human CD3-positive T cells, as determined by co-staining for the FLAG tag after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing the 9RC synthetic cytokine receptor or in primary human CD3- positive T cells that were untransduced (“UTD”). FIG.9A is a representative flow cytometry dot plot with CD57 staining on the y-axis and staining for FLAG on the x-axis. FIG.9B depicts the percent of CD8+ T cells that were high for CD57 expression (CD57hi) in UTD T cells or in 9RC+ transduced T cells.

[0135] FIG.10 shows the surface expression level of TIM3 and LAG3 in primary human CD3- positive T cells that were co-transduced with lentiviral vectors expressing the 9RC synthetic cytokine receptor and a CAR separated by either a 2A sequence (40bbz-2a-FLAG-9RC”) or a IRES sequence30761-20002.40 (40bbz-IRES-CD34-9RC), or in primary human CD3- positive T cells that were untransduced (“UTD”). A representative flow cytometry dot plot is shown with TIM3 staining on the y-axis and LAG3 staining on the x-axis.

[0136] FIG.11 shows the surface expression level of CD4 and CD8 in primary human CD3- positive T cells 5 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing an exemplary synthetic cytokine receptor (9RC, 9RC2, or 9RD2) or in primary human CD3-positive T cells that were untransduced.

[0137] FIG.12 illustrates the growth of primary human CD3-positive T cells expressing an exemplary synthetic cytokine receptor (9RC or 9RC2), the exemplary synthetic cytokine receptor 9RC co-expressed with a CAR (designated “40bbz-9RC”), or in untransduced (UTD) cells during extended in vitro culture. The results depict the day of culture post-activation and the fold growth at the respective day compared to the number of cells at the previous count for each condition.

[0138] FIGS.13A-13E show the design and expression of additional exemplary synthetic cytokine receptors comprising an IL7R TMD and an IL-9R ICD. Each additional synthetic receptor construct had a different extracellular domain (ECD) as follows: GpA (construct “G-7-9R”; FIG. 13A), truncated GpA (construct “tG-7-9R”; FIG.13B), CD8 (construct “CD8-7-9R”; FIG.13C), truncated CD8 (construct “tCD8-7-9R”; FIG.13D), or Muc24 (construct “M-7-9R”; FIG.13E).

[0139] FIGS.14A-14B show the design and expression of additional exemplary synthetic cytokine receptors comprising an IL-9R ICD and a transmembrane domain other than an IL7R TMD. FIG.14A depicts a synthetic cytokine construct with a Glycophorin A (GpA) ECD, a GpA TMD and an IL-9R ICD (“G-G-9R”). FIG.14B depicts a synthetic cytokine receptor with a Muc24 ECD, a Muc24 TMD and an IL-9R ICD (“M-M-9R”).

[0140] FIGS.15A-15H show the designs and expression data of additional exemplary synthetic cytokine receptors comprising an IL9R ICD, and full-length or truncated ECD from GpA, CD8 or Muc24 and a TMD from GpA, truncated GpA (designated GpA*), TACI, CPT1 or DR5. The depicted constructs include an ECD, TMD and ICD as follows: truncated GpA ECD, GpA TMD and IL9R ICD (construct “tGpA-G-9R”; FIG.15A), CD8 ECD, GpA TMD and IL9R ICD (construct “CD8-G- 9R”; FIG.15B), truncated CD8 ECD, GpA TMD and IL9R ICD (construct “tCD8-G-9R”; FIG. 15C), Muc24 ECD, GpA TMD and IL9R ICD (construct “M24-G-9R”; FIG.15D), truncated CD8 ECD, truncated GpA TMD and IL9R ICD (construct “tCD8-G*-9R”; FIG.15E), truncated CD7 ECD, TACI TMD and IL9R ICD (construct “tCD8-T-9R”; FIG.15F), truncated CD8 ECD, CPT1 TMD and IL9R ICD (construct “tCD8-C-9R”; FIG.15G), and truncated CD8 ECD, DR5 TMD and IL9R ICD (construct “tCD8-D-9R”; FIG.15H).

[0141] FIG.16 shows transduction efficiency of exemplary synthetic cytokine receptors in primary human CD3-positive T cells 5 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing the exemplary synthetic cytokine receptor or in30761-20002.40 untransduced T cells (UTD). Transduction efficiency was determined by flow cytometry by cell surface staining for cells positive for the Flag tag.

[0142] FIGS.17A-17C show the surface expression level of CD27 and CD45RA 5 days after the primary human CD3-positive T cells were transduced with lentiviral vectors expressing the exemplary synthetic cytokine receptors. The figure provides representative flow cytometry contour plots with CD45RA staining on the x-axis and CD27 staining on the y-axis.

[0143] FIG.18 shows in vivo survival of tumor-bearing mice administered primary human CD3- positive T cells co-expressing a CAR (40BBz) and an exemplary synthetic cytokine receptor, as compared to primary human CD3-positive T cells expressing the CAR only or that were un- transduced (UTD).

[0144] FIG.19 shows STAT phosphorylation (pSTAT) in primary human CD3-positive T cells expressing exemplary synthetic cytokine receptors. pSTAT was measured at 0 hours, 20 minutes, 2 hours, and 24 hours post-stimulation with cytokine.

[0145] FIG.20 shows the expression of an exemplary synthetic cytokine receptor on the surface of primary human CD3-positive T cells.

[0146] FIG.21 shows STAT phosphorylation (pSTAT) of STAT1, STAT3, and STAT5 in primary human CD3-positive T cells expressing exemplary synthetic cytokine receptors.

[0147] FIG.22 shows the number of HCT116 tumor cells per field of view (FOV) across time in a T cell-mediated killing assay. T cells were obtained from two healthy donors and cocultured with tumor cells at an effector:target (E:T) ratio of 1:2.

[0148] FIG.23 shows the number of HCT116 tumor cells per field of view (FOV) across time in a T cell-mediated killing assay. T cells were obtained from a healthy donor and cocultured with tumor cells at an effector:target (E:T) ratio of 1:4.

[0149] FIG.24 shows phenotype markers CD27 and CD45RA in primary T cells expressing exemplary synthetic cytokine receptors.

[0150] FIG.25 shows the total number of T cells co-expressing a CAR (40BBz) and a synthetic cytokine receptor at plating and after two rounds of T cell-mediated killing.

[0151] FIG.26 shows the percentage of CD8 T cells positive for cytokine expression after target stimulation. CD8 T cells either co-expressed a CAR (40BBz) and an exemplary synthetic cytokine receptor or a CAR alone. Measured cytokines included IL-2, IFN-Ȗ, and TNFĮ.

[0152] FIG.27 shows the percentage of live T cells after two rounds of stimulation. T cells co- expressing a CAR (40BBz) and synthetic cytokine receptor were cocultured with K562 cells expressing an antigen recognized by the CAR (40BBz).

[0153] FIGS.28A-28B show the percentage of T cells expressing a CAR (40BBz) and exemplary synthetic cytokine receptors post-transduction.9RC5 = C-7-9R(a); 9RC5.1 = CD8-7- 9R(c); 9RC5.2 = tCD8-7-9R(c).30761-20002.40

[0154] FIG.29 shows STAT phosphorylation (pSTAT) in primary human CD3-positive T cells co-expressing a CAR (40BBz) and exemplary synthetic cytokine receptors. pSTAT1, pSTAT3 and pSTAT5 are represented as a percentage of the highest signal observed for each of the individual STATs.

[0155] FIG.30 shows the percentage of CD8+ T cells expressing cytokines after 4-hour stimulation with target cells. CD8+ T cells either co-expressed a CAR (40BBz) and an exemplary synthetic cytokine receptor or only a CAR. Measured cytokines included IFN-Ȗ, IL-2, IL-10, and TNFĮ.

[0156] FIG.31 shows cytokine and effector molecule secretion by CD8+ T cells after 24-hour stimulation with target cells. CD8+ T cells either co-expressed a CAR (40BBz) and an exemplary synthetic cytokine receptor or only a CAR. Cytokine and effector molecule secretion are displayed as a percentage relative to the highest expressor of each analyte.

[0157] FIGS.32A-32B show CD45RA and CD27 staining of CD8+ T cells in a continuous co- culture with target cells. CD8+ T cells either co-expressed a CAR (40BBz) and an exemplary synthetic cytokine receptor or only a CAR. FIG.32A depicts CD45RA and CD27 expression across three weeks. FIG.32B depicts summary data for three technical replicates at the week three timepoint.

[0158] FIGS.33A-33C show live CD8+ T cell counts in a continuous co-culture with target cells. CD8+ T cells either co-expressed a CAR (40BBz) and an exemplary synthetic cytokine receptor or only a CAR. FIG.33A depicts live CD8+ T cell counts across three weeks. FIG.33B depicts live CD8+ T cells at week three. FIG.33C depicts CD39 expression in CD8+ T cells at week three.

[0159] FIG.34 shows expansion of CD8+ T cells cultured with or without IL-2 for four weeks. CD8+ T cells either co-expressed a CAR (40BBz) and an exemplary synthetic cytokine receptor or only a CAR.

[0160] FIG.35 shows tumor growth in tumor-bearing mice administered primary human CD3- positive T cells co-expressing a CAR (40BBz) and an exemplary synthetic cytokine receptor, as compared to primary human CD3-positive T cells expressing the CAR only or that were un- transduced (UTD). Tumor-bearing mice were administered 1 x 106cells.

[0161] FIG.36 shows tumor growth in tumor-bearing mice administered primary human CD3- positive T cells co-expressing a CAR (40BBz) and an exemplary synthetic cytokine receptor, as compared to primary human CD3-positive T cells expressing the CAR only or that were un- transduced (UTD). Tumor-bearing mice were administered 3 x 105cells. DETAILED DESCRIPTION

[0162] The present disclosure provides synthetic cytokine receptors capable of driving interleukin-9 (IL-9) receptor (IL-9R) signaling in the absence of its cognate cytokine ligand (i.e.,30761-20002.40 constitutively active). These synthetic cytokine receptors comprise an intracellular domain derived from the intracellular domain of human IL-9 receptor alpha (IL-9RĮ), which can activate STAT1, STAT3, and STAT5 and trigger a strong JAK / STAT signal cascade. These synthetic cytokine receptors also comprise various modified intracellular domains, transmembrane domains, and extracellular domains. Immune cells such as T cells expressing these synthetic cytokine receptors are advantageous because such T cells assume characteristics of stem memory T cells without exhibiting signs of malignant transformation. Such T cells can be used in adoptive immunotherapy.

[0163] In some embodiments, the mechanism of constitutive activation comprises multimerization of the extracellular domain. In some embodiments, the mechanism of constitutive activation comprises multimerization of the transmembrane domain. In some embodiments, the mechanism of constitutive activation comprises multimerization of the intracellular domain. In some embodiments, the mechanism of constitutive activation comprises multimerization of at least two domains (e.g., the extracellular domain and the transmembrane domain). In some embodiments, the mechanism of constitutive activation comprises multimerization of three domains (i.e., the extracellular domain, the transmembrane domain, and the intracellular domain).

[0164] Adoptively transferred genetically engineered immune cells (e.g., T cells) have shown substantial anti-tumor activity in patients with hematopoietic malignancies but have limited efficacy in solid tumors. This is due to the immunosuppressive environment of solid tumors, the inefficient infiltration of solid tumors, and chronic antigen stimulation, which leads to lack persistence and / or efficacy. In some cases, multipotency and replicative potential are also diminished. Thus, there is a need for compositions and / or methods that reduce or eliminate immune cell exhaustion, lack persistence, and / or decreased efficacy.

[0165] The provided disclosure addresses these needs. The present disclosure demonstrates that the provided synthetic chimeric IL-9 receptors, even in the absence of ligand, have the ability to constitutively activate cells in which they are expressed, such as T cells. In some embodiments, the activation triggers a strong JAK / STAT signal cascade where STAT1, STAT3, and STAT5 can all be activated. In some embodiments, the activation has the ability to result in T cells that overcome T cell exhaustion by polarizing T cells toward a naiver phenotype and skewing the ratio of CD4:CD8, such as to a ratio of 2:1, without triggering malignant transformation of T cells. Thus, the present disclosure demonstrates that the constitutive IL-9R disclosed herein has the potential to reprogram and alter the phenotype of immune cells to overcome exhaustion, which can improve anti-tumor activity in solid tumors. I. Definitions

[0166] Unless otherwise defined herein, technical, and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa unless the content30761-20002.40 clearly dictates otherwise. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control.

[0167] The terms “a”, “an”, and “the”, as used herein, include plural references unless the context clearly dictates otherwise.

[0168] The term “about”, as used herein, in reference to a number or range of numbers, is understood to mean the stated number and numbers + / - 10% thereof, or 10% below the lower listed limit and 10% above the higher listed limit for the values listed for a range.

[0169] The terms “or” and “and / or”, as used herein, include any, and all, combinations of one or more of the associated listed items.

[0170] The terms “including”, “includes”, “included”, and other forms, as used herein, are not limiting.

[0171] The terms “comprise” and its grammatical equivalents, as used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0172] The term “administer”, “administration”, or “administering”, as used herein refers to the act of injecting or otherwise physically delivering a substance (e.g., a pharmaceutical composition provided herein) to a subject (e.g., human), such as by oral, mucosal, topical, intradermal, parenteral, intravenous, intravitreal, intraarticular, subretinal, intramuscular, intrathecal delivery and / or any other method of physical delivery described herein or known in the art. The delivery can be systemic or to a specific tissue.

[0173] The term “binds” or “binding”, as used herein, refers to a covalent or non-covalent interaction between molecules (e.g., forming a complex by interactions). Exemplary non-covalent interactions include hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. With regard to terms such as “specific binding,” “specifically binds to,” or “is specific for” means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity.

[0174] The term “chimeric antigen receptor” or “CAR”, as used herein, refers to a genetically engineered receptor, which can be used to graft one or more antigen specificity onto immune effector cells, such as T cells and NK cells. CARs are also known as “artificial T-cell receptors,” “chimeric T cell receptors,” or “chimeric immune receptors.” “CAR-T cell” refers to a T cell that expresses a CAR. “CAR-NK cell” refers to an NK cell that expresses a CAR.

[0175] The term “constitutively active”, as used in the context of a receptor, refers to a receptor capable of activating downstream signaling (e.g., interleukin-9 signaling) in the absence of the cognate ligand of the receptor.30761-20002.40

[0176] The term “contact”, as used in the context of contacting a target cell with a compound or another cell, is intended to include incubating the target cell and the compound or the other cell together.

[0177] The term “effective amount” or “therapeutically effective amount”, as used herein, refers to an amount of a therapeutic (e.g., a pharmaceutical composition provided herein) which is sufficient to treat, diagnose, prevent, delay the onset of, reduce and / or ameliorate the severity and / or duration of a given condition, disorder, or disease and / or a symptom related thereto. The term also encompasses an amount necessary for the reduction, slowing, or amelioration of the advancement or progression of a given disease, reduction, slowing, or amelioration of the recurrence, development or onset of a given disease, and / or to improve or enhance the prophylactic or therapeutic effect (s) of another therapy or to serve as a bridge to another therapy.

[0178] The term “immune effector cell”, as used herein, refers to cells involved in mounting innate and adaptive immune responses, including but not limited to lymphocytes, natural killer (NK) cells, NKT cells, macrophages, monocytes, eosinophils, basophils, neutrophils, dendritic cells, and mast cells. In some embodiments, the immune effector cell is a lymphocyte. In some embodiments, the immune effector cell is a cytotoxic T cell, such as a CD4+ T cell, a CD8+ T cell (also referred to as a cytotoxic T cell or CTL), a regulatory T cell (Treg), a Th1 cell, a Th2 cell, or a Th17 cell.

[0179] The term “leucine zipper domain”, as used herein, refers to an amphipathic Į helix containing heptad repeats of Leu residues on one face of the helix and serves as a dimerization module. In some embodiments, the leucine zipper domain is an active leucine zipper domain. On dimerization with another leucine zipper domain, the leucine-zipper Į helices form a parallel-coiled coil based on hydrophobic interfacial side-chain packing. In some embodiments, the leucine zipper domain is an inactive leucine zipper domain that cannot form a dimer with another leucine zipper domain.

[0180] The term “naturally-occurring”, as applied to a nucleic acid, a polypeptide, a cell, or an organism, refers to a nucleic acid, polypeptide, cell, or organism that is found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by a human in the laboratory is naturally occurring.

[0181] The term “pharmaceutically acceptable excipient, carrier or diluent”, as used herein, refers to any substance formulated alongside the active ingredient of a pharmaceutical composition that allows the active ingredient to retain biological activity and is non-reactive with the subject’s immune system. Such a substance can be included for the purpose of long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts, or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating absorption, reducing viscosity, or enhancing solubility. The selection of appropriate substance can depend upon the route of administration and the dosage form, as well as the active ingredient and30761-20002.40 other factors. Compositions having such substances can be formulated by well-known conventional methods (see, e.g., Remington, The Science and Practice of Pharmacy, 23rd edition, A. Adejare, ed., Academic Press, 2020).

[0182] The term “pharmaceutical composition” or “therapeutic composition”, as used herein, refers to a composition capable of being administered to a subject for the treatment of a particular disease or disorder.

[0183] The term “polynucleotide” or “nucleic acid”, as used herein, refers to deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and DNA / RNA hybrids. Polynucleotides may be single-stranded or double-stranded and either recombinant, synthetic, or isolated. Polynucleotides include but are not limited to: pre-messenger RNA (pre-mRNA), messenger RNA (mRNA), RNA, genomic DNA (gDNA), PCR amplified DNA, complementary DNA (cDNA), synthetic DNA, or recombinant DNA. Polynucleotides can comprises modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. Unless specified otherwise, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5’ end; the left-hand direction of double-stranded polynucleotide sequences is referred to as the 5’ direction. The direction of 5’ to 3’ addition of nascent RNA transcripts is referred to as the transcription direction.

[0184] The terms “polypeptide” and “peptide” and “protein”, as used herein, refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid, including but not limited to, unnatural amino acids, as well as other modifications known in the art.

[0185] The term “population” of cells, as used herein, refers to any number of cells greater than 1, but is preferably at least about 1x103cells, at least about 1x104cells, at least about 1x105cells, at least about 1x106cells, at least about 1x107cells, at least about 1x108cells, at least about 1x109cells, at least about 1x1010cells, at least about 1x1011or more cells. A population of cells may refer to an in vitro population (e.g., a population of cells in culture) or an in vivo population (e.g., a population of cells residing in a particular tissue).

[0186] The term “sequence identity”, as used herein, refers to the percentage of bases or amino acids between two polynucleotide or polypeptide sequences that are the same, and in the same relative position. As such one polynucleotide or polypeptide sequence has a certain percentage of sequence identity compared to another polynucleotide or polypeptide sequence. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. The term “reference sequence” refers to a molecule to which a test sequence is compared. Methods of sequence30761-20002.40 alignment for comparison and determination of percent sequence identity and percent complementarity are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the homology alignment algorithm of Needleman and Wunsch, (1970) J. Mol. Biol.48:443, by the search for similarity method of Pearson and Lipman, (1988) Proc. Nat’l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), by manual alignment and visual inspection (see, e.g., Brent et al., (2003) Current Protocols in Molecular Biology), by use of algorithms know in the art including the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al., (1977) Nuc. Acids Res.25:3389-3402; and Altschul et al., (1990) J. Mol. Biol.215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score l 00, word length-! 2 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, word length-3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res., 1997, 25:3389-402. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI BLAST programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:1117. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0187] The term “subject”, as used herein, refers to an “animal” and in particular a “mammal” such as a non-primate (e.g., mice, rats, bovines, horses, household cats, tigers and other large cats, dogs, pigs, rabbits, goats, deer, sheep, ferrets, gerbils, guinea pigs, hamsters, bats, and birds (e.g., chickens, turkeys, and ducks)) or a primate (e.g., monkeys, baboons, chimpanzees, and human). The term may be used interchangeably with the term “patient” or “individual”. In some embodiments, the subject is a mammal, e.g., a human, diagnosed with a disease or disorder provided herein. In some embodiments, the subject is a mammal, e.g., a human, at risk of developing a disease or disorder provided herein. In some embodiments, the subject is human.

[0188] The term “synthetic”, as applied to a nucleic acid, a polypeptide, a cell, or an organism, refers to a nucleic acid, polypeptide, cell, or organism that cannot be directly isolated from a source in nature. In some embodiments, the synthetic nucleic acid, polypeptide, cell, or organism is30761-20002.40 substantially similar as compared to the corresponding natural-occurring one. In some embodiments, the synthetic nucleic acid, polypeptide, cell, or organism is altered or changed as compared to the corresponding natural-occurring one. In some embodiments, the synthetic nucleic acid, polypeptide, cell, or organism is produced by functionally linking or combining different fragments of sourcing nucleic acids, polypeptides, cells, or organisms together. For instance, a synthetic polypeptide can comprise different sourcing polypeptides functionally linked together.

[0189] The terms “treatment” and “treating”, as used herein, refer to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0190] The term “vector”, as used herein, refers to a substance that is used to carry or introduce a nucleic acid sequence (e.g., a nucleic acid sequence encoding a synthetic cytokine receptor as described herein) into a host cell. Vectors applicable for use include, for example, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes. A vector may include sequences that direct autonomous replication in a cell or may include sequences sufficient to allow integration into host cell DNA. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes that can be included, for example, provide resistance to antibiotics or toxins, complement auxotrophic deficiencies, or supply critical nutrients not in the culture media. Expression control sequences can include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like, which are well known in the art. When two or more nucleic acid molecules are to be co-expressed (e.g., both an antibody heavy and light chain or an antibody VH and VL), both nucleic acid molecules can be inserted, for example, into a single expression vector or in separate expression vectors. For single vector expression, the encoding nucleic acids can be operationally linked to one common expression control sequence or linked to different expression control sequences. The introduction of nucleic acid molecules into a host cell can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis such as Northern blots or polymerase chain reaction (PCR) amplification of mRNA, immunoblotting for expression of gene products, or other suitable analytical methods to test30761-20002.40 the expression of an introduced nucleic acid sequence or its corresponding gene product. It is understood by those skilled in the art that the nucleic acid molecules are expressed in a sufficient amount to produce a desired product and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.

[0191] General methods in molecular and cellular biochemistry can be found in such standard textbooks as Molecular Cloning: A Laboratory Manual, 3rd Ed. (Sambrook et al., HaRBor Laboratory Press 2001 ); Short Protocols in Molecular Biology, 4th Ed. (Ausubel et al. eds., John Wiley & Sons 1999); Protein Methods (Bollag et al., John Wiley & Sons 1996); Nonviral Vectors for Gene Therapy (Wagner et al. eds., Academic Press 1999); Viral Vectors (Kaplift & Loewy eds., Academic Press 1995); Immunology Methods Manual (I. Lefkovits ed., Academic Press 1997); and Cell and Tissue Culture: Laboratory Procedures in Biotechnology (Doyle & Griffiths, John Wiley & Sons 1998), the disclosures of which are incorporated herein by reference. II. Synthetic Cytokine Receptor

[0192] Provided herein is a synthetic cytokine receptor. In some embodiments, the synthetic cytokine receptor is capable of interleukin 9 receptor (IL-9R) signaling.

[0193] In some embodiments, the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain. In some embodiments, the synthetic cytokine receptor provided herein can multimerize, typically as a homodimer, to facilitate downstream signaling in the absence of external stimuli of the receptor, such as in the absence of binding of a ligand to the extracellular domain. Thus, in some embodiments, the synthetic cytokine receptor is constitutively active. In some embodiments, multimerization (e.g, dimerization) of a synthetic cytokine receptor allows the receptor to be constitutively active by orienting polypeptide chains of the receptor so that JAK / STAT signaling molecules are recruited thereto for subsequent activation. Typically, IL-9R signaling requires binding of its cytokine to the IL-9R alpha chain to promote heterodimerization with the common gamma chain subunit, activation of JAK kinases (e.g., JAK1 and JAK3) for association with and phosphorylation of the receptor chains, and subsequent phosphorylation and recruitment of other signaling molecules such as STAT transcription factors, in particular STAT1, STAT3 and STAT5. In provided embodiments, synthetic receptor spontaneously form homo-multimers, such as homodimers, that constitutively activate JAK signaling resulting in activation of STAT1, STAT3 and / or STAT5, including translocation of homodimers of STAT-1, STAT-3 or STAT-5 as well as their heterodimers (e.g., STAT-1 / STAT-3) to the nucleus for regulating gene expression.

[0194] In some embodiments, engineered cells (e.g., T cells) expressing the synthetic cytokine receptors provided herein, and in some cases also expressing a chimeric antigen receptor (CAR), maintain the ability to proliferate even in the absence of a ligand of the extracellular domain (e.g., absence of a cytokine).30761-20002.40

[0195] In some embodiments, the synthetic cytokine receptor comprises a multimer. In some embodiments, the multimer is a dimer.

[0196] In some embodiments, the synthetic cytokine receptor multimerizes in higher orders (e.g., trimer, tetramer, or higher). In some embodiments, the synthetic cytokine receptor multimerizes as a trimer, tetramer, pentamer, hexamer, heptamer, octamer, nonamer or decamer. In some embodiments, the multimer is a trimer. In some embodiments, the multimer is a tetramer. In some embodiments, the multimer is a pentamer. In some embodiments, the multimer is a hexamer. In some embodiments, the multimer is a heptamer. In some embodiments, the multimer is an octamer. In some embodiments, the multimer is a nonamer. In some embodiments, the multimer is a decamer. In some embodiments, the multimer is an undecamer. In some embodiments, the multimer is a dodecamer.

[0197] In some embodiments, the multimer comprises identical polypeptide chains, each comprising the extracellular domain, the transmembrane domain, and the IL-9R intracellular domain. In some embodiments, the multimer is a homo-multimer. In some embodiments, the homo-multimer is a homo-dimer. In some embodiments, the homo-multimer is a homo-trimer. In some embodiments, the homo-multimer is a homo-tetramer. In some embodiments, the homo-multimer is a homo- pentamer. In some embodiments, the homo-multimer is a homo-hexamer. In some embodiments, the homo-multimer is a homo-heptamer. In some embodiments, the homo-multimer is a homo-octamer. In some embodiments, the homo-multimer is a homo-nonamer. In some embodiments, the homo- multimer is a homo-decamer. In some embodiments, the homo-multimer is a homo-undecamer. In some embodiments, the homo-multimer is a homo-dodecamer. In some embodiments, the multimer is a hetero-multimer.

[0198] In some embodiments, the synthetic cytokine receptor is multimerized through the extracellular domain, transmembrane domain, and / or IL-9R intracellular domain. In some embodiments, the synthetic cytokine receptor is multimerized through the extracellular domain. In some embodiments, the synthetic cytokine receptor is multimerized through the transmembrane domain. In some embodiments, the synthetic cytokine receptor is multimerized through the IL-9R intracellular domain. In some embodiments, the synthetic cytokine receptor is multimerized through both the extracellular domain and the transmembrane domain. In some embodiments, the synthetic cytokine receptor is multimerized through both the transmembrane domain and the IL-9R intracellular domain. In some embodiments, the synthetic cytokine receptor is multimerized through both the extracellular domain and the IL-9R intracellular domain. In some embodiments, the synthetic cytokine receptor is multimerized through the extracellular domain, the transmembrane domain, and the IL-9R intracellular domain.

[0199] In some embodiments, the synthetic cytokine receptor is a constitutively active cytokine receptor. In some embodiments, the synthetic cytokine receptor is a multimer of polypeptide chains that is constitutively multimerized. In some embodiments, a constitutively multimerized synthetic cytokine receptor is constitutively active. In some embodiments, the multimerized synthetic cytokine30761-20002.40 receptor is constitutively active because each polypeptide chain of the multimer permits multimerization without the need for external stimuli of the receptor. In some embodiments, the constitutively multimerized synthetic cytokine receptor elicits signaling through a STAT pathway.

[0200] In some embodiments, an advantage of the synthetic cytokine receptors provided herein is that the receptors are constitutively active in the absence of ligand. That is, downstream IL-9R signaling is constitutive in the absence of ligand binding to the ECD of the synthetic cytokine receptor. However, ligand binding to the ECD of the synthetic cytokine receptors provided herein is not precluded. In some embodiments, the ECD of the synthetic cytokine receptors provided herein bind their cognate ligand. However, constitutive signaling of a provided synthetic cytokine receptor is not dependent on ECD ligand binding. Thus, in some embodiments, the synthetic cytokine receptors provided herein are constitutively active in the absence and presence of one or more ligands. In some embodiments, the synthetic cytokine receptors provided herein are constitutively active in the presence or absence of any ligand. In particular embodiments, when the ECD of the synthetic cytokine receptors provided herein is derived from a CD34 receptor, the synthetic cytokine receptor is constitutively active in the presence or absence of CD34 receptor ligand. In particular embodiments, when the ECD of the synthetic cytokine receptors provided herein is derived from a DAP12 receptor, the synthetic cytokine receptor is constitutively active in the presence or absence of DAP12 receptor ligand. In particular embodiments, when the ECD of the synthetic cytokine receptors provided herein is derived from a GpA receptor, the synthetic cytokine receptor is constitutively active in the presence or absence of GpA receptor ligand. In particular embodiments, when the ECD of the synthetic cytokine receptors provided herein is derived from a CD8 receptor, the synthetic cytokine receptor is constitutively active in the presence or absence of CD8 receptor ligand. In particular embodiments, when the ECD of the synthetic cytokine receptors provided herein is derived from a Muc24 receptor, the synthetic cytokine receptor is constitutively active in the presence or absence of Muc24 receptor ligand. In particular embodiments, the ECD does not substantially bind, such as does not bind specifically or with high affinity, the native ligand of the receptor from which the ECD is derived. In some embodiments, the native ligand of the receptor from which the ECD is derived does not bind the ECD of the synthetic cytokine receptor in a manner that could modulate intracellular signaling (e.g., STAT signaling) by the synthetic cytokine receptor. In particular embodiments, the synthetic cytokine receptors provided herein elicit IL-9R signaling in the absence of IL-9. In some embodiments, the synthetic cytokine receptors provided herein do not bind IL-9.

[0201] In some embodiments, the constitutively multimerized synthetic cytokine receptor is a constitutively active cytokine receptor that elicits signaling through STAT1, STAT3 or STAT5 pathway. In some embodiments, the constitutively multimerized synthetic cytokine receptor elicits signaling through STAT1 pathway. In some embodiments, the multimerized synthetic cytokine receptor elicits signaling through STAT3 pathway. In some embodiments, the constitutively multimerized synthetic cytokine receptor elicits signaling through STAT5 pathway. In some30761-20002.40 embodiments, the constitutively multimerized synthetic cytokine receptor elicits signaling through STAT1, STAT3, and STAT5 pathways at the same time. In some embodiments, the constitutively multimerized synthetic cytokine receptor elicits signaling through STAT1, STAT3, and STAT5 pathways sequentially in any order. Signaling through STAT1, STAT3, and / or STAT5 can be determined by any method known in the art. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 is determined by detecting phosphorylated STAT1, STAT3 and / or STAT5. As an example, STAT1, STAT3 and / or STAT5 phosphorylation can be detected by Western blot with antibodies that specifically bind to phosphorylated STAT1, STAT3, and / or STAT5.

[0202] In some embodiments, the synthetic cytokine receptor that multimerizes in higher orders (e.g, timer, tetramer or higher) elicits stronger signaling when compared to dimerized synthetic cytokine receptor. In some embodiments, the elicited signaling of the higher ordered multimerized synthetic cytokine receptor is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% stronger than the dimerized synthetic cytokine receptor. In some embodiments, the elicited signaling of the higher ordered multimerized synthetic cytokine receptor is at least about 1 time, at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, or at least about 9 times stronger than the dimerized synthetic cytokine receptor. In some embodiments, the elicited signaling of a trimer, tetramer, pentamer, hexamer, heptamer, octamer, nonamer, decamer, undecamer, and / or dodecamer synthetic cytokine receptor is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% stronger than the dimerized synthetic cytokine receptor. In some embodiments, the elicited signaling of a trimer, tetramer, pentamer, hexamer, heptamer, octamer, nonamer, decamer, undecamer, and / or dodecamer synthetic cytokine receptor is at least about 1 time, at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, or at least about 9 times stronger than the dimerized synthetic cytokine receptor.

[0203] In some embodiments, stronger signaling can be demonstrated by sustained or prolonged STAT activation. In some embodiments, STAT activation can be shown by detecting phosphorylated STAT. In some embodiments, STAT1, STAT3, and / or STAT5 phosphorylation can be detected by Western blot with antibodies that specifically bind to phosphorylated STAT1, STAT3, and / or STAT5. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 can be determined by any method known in the art.

[0204] In some embodiments, synthetic cytokine receptor multimerization occurs through a covalent or noncovalent interaction.

[0205] In some embodiments, synthetic cytokine receptor multimerization occurs through a covalent interaction. In some embodiments, each synthetic cytokine receptor is linked to each other30761-20002.40 via one or more covalent links within the multimer. In some embodiments, the covalent link is a disulfide bond. In some embodiments, the disulfide bond is formed between cysteine residues.

[0206] In some embodiments, the synthetic cytokine receptor comprises a self-assembly domain to promote multimerization of the receptor. Self-assembly is the spontaneous association of an ensemble of molecules into one or more supramolecular structures, driven by multiple noncovalent interactions. In some embodiments, synthetic cytokine receptor multimerization occurs through a noncovalent interaction. In some embodiments, the noncovalent interaction is promoted by an amino acid sequence motif. In some embodiments, the amino acid sequence motif promotes alpha-helix dimerization or multimerization. In some embodiments, the amino acid sequence motif promotes leucine-zipper dimerization or multimerization.

[0207] It is understood that reference to amino acids, including to a specific sequence set forth as a SEQ ID NO used to describe domain organization (e.g. of a extracellular domain, transmembrane domain or intracellular domain) are for illustrative purposes and are not meant to limit the scope of the embodiments provided. It is understood that polypeptides and the description of domains thereof are theoretically derived based on homology analysis and alignments with similar molecules. Thus, the exact locus can vary, and is not necessarily the same for each protein. Hence, a specific domain can be several amino acids (such as one, two, three or four) longer or shorter. Typically, it will be understood that any transmembrane domain(s) identified for the polypeptides herein are identified pursuant to criteria routinely employed in the art for identifying that type of hydrophobic domain. The exact boundaries of a transmembrane domain may vary but most likely by no more than about 5 amino acids at either end of the domain as initially identified. In some embodiments, the extracellular domain, when it is free of the transmembrane and cytoplasmic domains, is one that may be soluble (i.e. is not membrane bound). It is understood that the intracellular signaling domain is a IL-9R sequence or a variant or portion thereof that exhibits ability to elicit intracellular signaling such as by recruiting JAK and STAT molecules (e.g., STAT1, STAT3 and STAT5).

[0208] In some embodiments, the different domains (i.e., extracellular domain, transmembrane domain and intracellular domain) of the synthetic cytokine receptor are operatively linked. In some embodiments, the different elements are directly linked to each other. In some embodiments, the different elements are linked via a peptide linker, such as a (GxS)n linker, wherein x can be an integer between 1 and 10, and n can be an integer between 2 and 20. Additional linkers are known to a skilled artisan. A. Extracellular Domain

[0209] In some embodiments, the extracellular domain comprises the extracellular domain of a naturally occurring protein. In some embodiments, the extracellular domain comprises a fragment or a truncated portion of the extracellular domain of a naturally occurring protein.

[0210] In some embodiments, the extracellular domain in a provided synthetic cytokine receptor allows the synthetic cytokine receptor to be constitutively active by permitting multimerization (e.g.,30761-20002.40 dimerization) of its polypeptide chains to allow the downstream intracellular domains of the polypeptide chains to recruit JAK / STAT molecules in the absence of an external stimuli, such as in the absence of binding ligand to the extracellular domain.

[0211] In some embodiments, the extracellular domain may or may not be from the same natural molecule as the transmembrane domain to which it is operably linked. In some embodiments, the extracellular domain is from the same molecule as its corresponding transmembrane domain. In some embodiments, the extracellular domain is not from the same molecule as its corresponding transmembrane domain.

[0212] In some embodiments, the extracellular domain comprises one or more mutations compared to its corresponding wild-type protein. In some embodiments, a mutation may comprise a substitution, insertion, deletion, or any combination thereof.

[0213] In some embodiments, the extracellular domain interacts with one or more additional extracellular domains to promote the multimerization of the synthetic cytokine receptor.

[0214] In some embodiments, the extracellular domain stabilizes the synthetic cytokine receptor expressed on the surface of a cell. In some embodiments, the extracellular domain increases downstream signaling triggered by IL-9R intracellular domain. In some embodiments extracellular domain imparts a sink or ligand trap function, such as binding up of one or more molecules that would be harmful to the cells expressing the synthetic cytokine receptor. In some embodiments, the ligand is immunosuppressive. Examples of harmful ligands include TGF-beta, PD-Ll, IL-4, IL-13, IL-8, and IL-10.

[0215] In some embodiments, the extracellular domain disclosed herein is capable of binding a ligand but the ligand’s signal is not transmitted.

[0216] In some embodiments, the size of the extracellular domain is at least about 30 amino acids. In some embodiments, the size of the extracellular domain is at most about 300 amino acids in length. In some embodiments, the size of the extracellular domain is about 30 amino acids to about 300 amino acids. In some embodiments, the size of the extracellular domain is about 30 amino acids to about 50 amino acids, about 30 amino acids to about 70 amino acids, about 30 amino acids to about 90 amino acids, about 30 amino acids to about 110 amino acids, about 30 amino acids to about 130 amino acids, about 30 amino acids to about 150 amino acids, about 30 amino acids to about 170 amino acids, about 30 amino acids to about 190 amino acids, about 30 amino acids to about 210 amino acids, about 30 amino acids to about 250 amino acids, about 30 amino acids to about 300 amino acids, about 50 amino acids to about 70 amino acids, about 50 amino acids to about 90 amino acids, about 50 amino acids to about 110 amino acids, about 50 amino acids to about 130 amino acids, about 50 amino acids to about 150 amino acids, about 50 amino acids to about 170 amino acids, about 50 amino acids to about 190 amino acids, about 50 amino acids to about 210 amino acids, about 50 amino acids to about 250 amino acids, about 50 amino acids to about 300 amino acids, about 70 amino acids to about 90 amino acids, about 70 amino acids to about 110 amino acids, about 70 amino30761-20002.40 acids to about 130 amino acids, about 70 amino acids to about 150 amino acids, about 70 amino acids to about 170 amino acids, about 70 amino acids to about 190 amino acids, about 70 amino acids to about 210 amino acids, about 70 amino acids to about 250 amino acids, about 70 amino acids to about 300 amino acids, about 90 amino acids to about 110 amino acids, about 90 amino acids to about 130 amino acids, about 90 amino acids to about 150 amino acids, about 90 amino acids to about 170 amino acids, about 90 amino acids to about 190 amino acids, about 90 amino acids to about 210 amino acids, about 90 amino acids to about 250 amino acids, about 90 amino acids to about 300 amino acids, about 110 amino acids to about 130 amino acids, about 110 amino acids to about 150 amino acids, about 110 amino acids to about 170 amino acids, about 110 amino acids to about 190 amino acids, about 110 amino acids to about 210 amino acids, about 110 amino acids to about 250 amino acids, about 110 amino acids to about 300 amino acids, about 130 amino acids to about 150 amino acids, about 130 amino acids to about 170 amino acids, about 130 amino acids to about 190 amino acids, about 130 amino acids to about 210 amino acids, about 130 amino acids to about 250 amino acids, about 130 amino acids to about 300 amino acids, about 150 amino acids to about 170 amino acids, about 150 amino acids to about 190 amino acids, about 150 amino acids to about 210 amino acids, about 150 amino acids to about 250 amino acids, about 150 amino acids to about 300 amino acids, about 170 amino acids to about 190 amino acids, about 170 amino acids to about 210 amino acids, about 170 amino acids to about 250 amino acids, about 170 amino acids to about 300 amino acids, about 190 amino acids to about 210 amino acids, about 190 amino acids to about 250 amino acids, about 190 amino acids to about 300 amino acids, about 210 amino acids to about 250 amino acids, about 210 amino acids to about 300 amino acids, or about 250 amino acids to about 300 amino acids. In some embodiments, the size of the extracellular domain is about 30 amino acids, about 50 amino acids, about 70 amino acids, about 90 amino acids, about 110 amino acids, about 130 amino acids, about 150 amino acids, about 170 amino acids, about 190 amino acids, about 210 amino acids, about 250 amino acids, or about 300 amino acids.

[0217] In some embodiments, the size of the extracellular domain is about 10 amino acids to about 260 amino acids in length. In some embodiments, the size of the extracellular domain is about 60 amino acids to 260 amino acids in length. In some embodiments, the size of the extracellular domain is about 69 amino acids in length. In some embodiments, the size of the extracellular domain is about 72 amino acids in length. In some embodiments, the size of the extracellular domain is about 139 amino acids in length. In some embodiments, the size of the extracellular domain is about 259 amino acids in length.

[0218] In some embodiments, the extracellular domain comprises a dimerizing domain. In some embodiments, the dimerizing domain comprises a hinge region. In some embodiments, the extracellular domain promotes disulfide-linked dimerization. In some embodiments, disulfide-linked dimerization is caused or facilitated by one or more cysteine residues. In some embodiments, the extracellular domain comprises 1 to 6 cysteine residues. In some embodiments, the extracellular30761-20002.40 domain comprises 1 cysteine residue. In some embodiments, the extracellular domain comprises 2 cysteine residues. In some embodiments, the extracellular domain comprises 3 cysteine residues. In some embodiments, the extracellular domain comprises 4 cysteine residues. In some embodiments, the extracellular domain comprises 5 cysteine residues. In some embodiments, the extracellular domain comprises 6 cysteine residues. In some embodiments, the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization forms 1 disulfide bridge between the polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization forms 2 disulfide bridges between the polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization forms 3 disulfide bridges between the polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization domain forms 4 disulfide bridges between the polypeptide chains of the synthetic cytokine receptor.

[0219] In some embodiments, the extracellular domain comprises an extracellular domain derived from CD8, CD34, Muc24, DAP12, or Glycophorin A (GpA). In some embodiments, the extracellular domain is derived from the extracellular domain of CD34. In some embodiments, the extracellular domain is derived from the extracellular domain of DAP12. In some embodiments, the extracellular domain is derived from the extracellular domain of Glycophorin A. In some embodiments, the extracellular domain is derived from the extracellular domain of CD8. In some embodiments, the extracellular domain is derived from the extracellular domain of Muc24.

[0220] In some embodiments, the extracellular domain comprises an extracellular domain of CD8 or a truncated portion thereof. In some embodiments, the CD8 extracellular domain comprises at least one cysteine residue.

[0221] In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 18. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 18.

[0222] In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about30761-20002.40 88% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the CD8 extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 18.

[0223] In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 19. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about30761-20002.40 90% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the CD8 extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 185. In some embodiments, the CD8 extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 185. In some embodiments, the CD8 extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 185.

[0224] In some embodiments, the extracellular domain comprises an extracellular domain of CD34 or a truncated portion thereof. In some embodiments, the CD34 extracellular domain comprises at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 4. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 4.

[0225] In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain30761-20002.40 comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the CD34 extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 4.

[0226] In some embodiments, the extracellular domain is an extracellular domain of Muc24 or a truncated portion thereof. In some embodiments, the Muc24 extracellular domain comprises at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 20. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 20.

[0227] In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 20. In some embodiments, the Muc2430761-20002.40 extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the Muc24 extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 20.

[0228] In some embodiments, the extracellular domain is an extracellular domain of DAP12 or a truncated portion thereof. In some embodiments, the DAP12 extracellular domain comprises at least one cysteine residue. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 5. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 5.

[0229] In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 5. In some embodiments, the DAP1230761-20002.40 extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 5. In some embodiments, the DAP12 extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 5.

[0230] In some embodiments, the extracellular domain is an extracellular domain of GpA or a truncated portion thereof. In some embodiments, the GpA extracellular domain comprises at least one cysteine residue.

[0231] In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 16. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 16.

[0232] In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino30761-20002.40 acids that is at least about 86% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 16. In some embodiments, the GpA extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the GpA extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 16.

[0233] In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 17. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 17.

[0234] In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ30761-20002.40 ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 17. In some embodiments, the GpA extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the GpA extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 17.

[0235] In some embodiments, the extracellular domain is an active leucine zipper domain of a transcription factor. In some embodiments, the transcription factor is a basic leucine zippers (bZIP). Non-limiting examples of bZIP transcription factors that can be used herein include ATF, JUN, CREB, Fos. In some embodiments, the extracellular domain is the leucine zipper domain of ATF. In some embodiments, the extracellular domain is the leucine zipper domain of JUN. In some embodiments, the extracellular domain is the leucine zipper domain of CREB. In some embodiments, the extracellular domain is the leucine zipper domain of Fos.

[0236] In some embodiments, the leucine zipper comprises Leu-X6-Leu-X6-Leu-X6-Leu (SEQ ID NO: 72). In some embodiments, the leucine zipper comprises MKQIEDKLEEILSKLYHIENELARIKKLLGE (SEQ ID NO: 73). In some embodiments, the leucine zipper comprises MKQIEDKIEEILSKIYHIENEIARIKKLIGE (SEQ ID NO: 74).

[0237] In some embodiments, the extracellular domain is an extracellular domain of Thrombopoietin Receptor (TpoR) or a truncated portion thereof. In some embodiments, the extracellular domain is a truncated portion of TpoR. In some embodiments, the truncated TpoR extracellular domain comprises deletion of up to 100, 150, 200, 250, 300, 350, 400, 450, or 500 amino30761-20002.40 acid residues from the N-terminus of wild-type TpoR extracellular domain set forth in SEQ ID NO: 178).

[0238] In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 178. In some embodiments, the TpoR extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 178. In some embodiments, the TpoR extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 178. In some embodiments, the extracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 162. In some embodiments, the extracellular domain comprises an amino acid sequence of SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 162. In some30761-20002.40 embodiments, the TpoR extracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 162. In some embodiments, the TpoR extracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 162.

[0239] In some embodiments, the extracellular domain provided herein can comprise any one of the extracellular domains set forth in Table 1. As indicated, the exact locus or residues corresponding to a given domain can vary, such as depending on the methods used to identify or classify the domain. Also, in some cases, adjacent N- and / or C-terminal amino acids of a given extracellular domain also can be included in a sequence of a synthetic cytokine receptor, so long as the resulting synthetic cytokine receptor is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules. Thus, it is understood that the exemplification of the SEQ ID NOS in Table 1 is not to be construed as limiting. For example, the particular extracellular domain can be several amino acids longer or shorter, such as 1-10, e.g., 1, 2, 3, 4, 5, 6 or 7 amino acids longer or shorter, than the sequence of amino acids set forth in the respective SEQ ID NO. Also provided are variants of any such SEQ ID NO (e.g., sequence that exhibits at least about 90% identity, at least about 91% identity, at least about 92% identity, at least about 93% identity, at least about 94% identity, at least about 95% identity, such as at least about 96% identity, 97% identity, 98% identity, or 99% identity to any one of SEQ ID NOS: 4, 5, 16, 17, 18, 19, 20, 73, 74, 162, 178 or 185), in which the resulting synthetic cytokine receptor containing such a variant extracellular domain is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules.B. Transmembrane Domain

[0240] In some embodiments, the transmembrane domain of the synthetic cytokine receptor comprises the transmembrane domain of a naturally occurring protein. In some embodiments, the transmembrane domain comprises a fragment or a truncated portion of the transmembrane domain of a naturally occurring protein.30761-20002.40

[0241] In some embodiments, the transmembrane domain in a provided synthetic cytokine receptor allows the synthetic cytokine receptor to be constitutively active by permitting multimerization (e.g., dimerization) of its polypeptide chains to allow the downstream intracellular domains of the polypeptide chains to recruit JAK / STAT molecules in the absence of an external stimuli, such as in the absence of binding ligand to the extracellular domain.

[0242] In some embodiments, the transmembrane domain may or may not be from the same natural molecule as either the extracellular domain to which it is operably linked. In particular embodiments the transmembrane is not from the same natural molecule as the extracellular domain to which it is operably linked.

[0243] In some embodiments, the transmembrane domain comprises one or more mutations compared to the transmembrane domain of its corresponding wild-type protein. In some embodiments, the one or more mutations promote, cause, or facilitate the multimerization of the transmembrane domain compared to its corresponding wildtype protein. In some embodiments, the transmembrane domain comprises one or more mutations that change the configuration of the downstream intracellular domain compared to its corresponding wildtype protein. In some embodiments, the transmembrane domain comprises one or more mutations that cause or facilitate the multimerization of the transmembrane domain and change the configuration of the downstream intracellular domain. Upon multimerization and / or change of configuration, the downstream IL-9R intracellular domain is oriented relative to each other in a manner that is conducive to signaling.

[0244] The mutation(s) may be a substitution, insertion, deletion, or combination thereof. In some embodiments, the one or more mutations comprises at least one cysteine. In some embodiments, the one or more mutations comprises at least one proline. Methods of determining whether a particular mutation will trigger the downstream signaling is known to a skilled artisan (e.g., assaying for STAT1, STAT3, or STAT5 phosphorylation following growth of the cells harboring the receptor being tested in the absence of growth factors).In some embodiments, the one or more mutations of a transmembrane domain is introduction of at least one cysteine residue. In some embodiments, introduction of at least one cysteine residue, such as by amino acid substitution, induces disulfide bond formation in the transmembrane domain. In some embodiments, the one or more mutations does not include introduction of a cysteine. For example, a variant transmembrane domain may be utilized that does not have a cysteine insertion(s) or amino acid substitution (such as for a disulfide bond with an adjacent polypeptide chain) but that still signals and is constitutively active, for example because the mutation rendered the transmembrane domain conformationally changed compared to a natural version of the transmembrane domain, thereby allowing induction of signaling. For example, insertion or amino acid substitution of an amino acid such as a proline produces a "kink" that twists the transmembrane domain, which can induce signaling (see, e.g., Shochat et al, 2011, J Exp Med.2011 May 9;208(5):901-8; Zenatti et al, 2011, Nat Genet.2011 Sep 4;43(10):932-9). In some embodiments, the one or more mutations of a transmembrane domain is introduction of a proline residues. In some30761-20002.40 embodiments, the mutation is, or comprises, the insertion or amino acid substitution of one or more cysteines, and / or one or more prolines. In some embodiments, the mutation is by introduction (e.g., insertion or amino acid substitution) of a trimer peptide of cysteine, proline, and another amino acid other than cystine or proline (e.g., threonine) into the transmembrane domain. In some embodiments, a trimer peptide confers the disulfide bond formation between the -SH (thiol) groups of cysteine residues of two molecules, allowing a homodimer to form between them (the proline immediately following the cysteine helps to twist the homodimer into the correct orientation, in specific embodiments). In some embodiments, the trimer peptide is a trimer peptide of cysteine, proline and threonine, in some cases a CPT insertion or in some cases a TCP insertion.

[0245] In some embodiments, the size of the transmembrane domain is at least about 15 amino acids. In some embodiments, the size of the transmembrane domain is about 15 amino acids to about 45 amino acids. In some embodiments, the size of the transmembrane domain is at most about 45 amino acids. In some embodiments, the size of the transmembrane domain is about 15 amino acids to about 20 amino acids, about 15 amino acids to about 25 amino acids, about 15 amino acids to about 30 amino acids, about 15 amino acids to about 35 amino acids, about 15 amino acids to about 40 amino acids, about 15 amino acids to about 45 amino acids, about 20 amino acids to about 25 amino acids, about 20 amino acids to about 30 amino acids, about 20 amino acids to about 35 amino acids, about 20 amino acids to about 40 amino acids, about 20 amino acids to about 45 amino acids, about 25 amino acids to about 30 amino acids, about 25 amino acids to about 35 amino acids, about 25 amino acids to about 40 amino acids, about 25 amino acids to about 45 amino acids, about 30 amino acids to about 35 amino acids, about 30 amino acids to about 40 amino acids, about 30 amino acids to about 45 amino acids, about 35 amino acids to about 40 amino acids, about 35 amino acids to about 45 amino acids, or about 40 amino acids to about 45 amino acids. In some embodiments, the size of the transmembrane domain is about 15 amino acids, about 20 amino acids, about 25 amino acids, about 30 amino acids, about 35 amino acids, about 40 amino acids, or about 45 amino acids.

[0246] In some embodiments, the transmembrane domain is about 21 amino acids, about 22 amino acids, about 23 amino acids, about 24 amino acids, about 25 amino acids, about 26 amino acids, about 27 amino acids, about 28 amino acids, about 29 amino acids, about 30 amino acids, about 31 amino acids, about 32 amino acids or about 33 amino acids in length. In some embodiments, the transmembrane domain is 21 amino acids in length. In some embodiments, the transmembrane domain is 22 amino acids in length. In some embodiments, the transmembrane domain is 23 amino acids in length. In some embodiments, the transmembrane domain is 24 amino acids in length. In some embodiments, the transmembrane domain is 25 amino acids in length. In some embodiments, the transmembrane domain is 26 amino acids in length. In some embodiments, the transmembrane domain is 27 amino acids in length. In some embodiments, the transmembrane domain is 28 amino acids in length. In some embodiments, the transmembrane domain is 29 amino acids in length. In some embodiments, the transmembrane domain is 30 amino acids in length. In some embodiments,30761-20002.40 the transmembrane domain is 31 amino acids in length. In some embodiments, the transmembrane domain is 32 amino acids in length. In some embodiments, the transmembrane domain is 33 amino acids in length.

[0247] In some embodiments, the transmembrane domain promotes dimerization.

[0248] In some embodiments, the transmembrane domain is derived from the transmembrane domain of interleukin 7 receptor. In some embodiments, the transmembrane domain is derived from the transmembrane domain of Glycophorin A. In some embodiments, the transmembrane domain is derived from the transmembrane domain of Muc24.

[0249] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA) Carnitine palmitoyltransferase 1 (CPT1), or a tumor necrosis factor receptor (TNFR) or Muc24. In some embodiments, the transmembrane domain is a variant or a truncated form of a transmembrane domain derived from Glycophorin A (GpA) Carnitine palmitoyltransferase 1 (CPT1), or a tumor necrosis factor receptor (TNFR) or Muc24.

[0250] In some embodiments, the transmembrane domain promotes alpha-helix dimerization. In some embodiments, alpha-helix oligomerization, such as dimerization or trimerization, is driven by sequence motifs, which are simple recognizable amino acid sequences that promote lateral interaction. In some embodiments, the transmembrane domain contains a proline rich motif ĭPXĭ (SEQ ID NO: 75), in which ĭ represents a hydrophobic residue, P is proline and X can be any amino acid, typically an apolar residue except for proline and glycine. In some embodiments, the transmembrane domain contains a ĭTXXAĭ, in which ĭ represents a hydrophobic residue, T is threonine, X can be any amino acid, typically an apolar residue except for proline and glycine, and A is alanine. In some embodiments, the transmembrane domain contains a GXXXG motif (SEQ ID NO:68). In some embodiments, the transmembrane domain contains a GXXXA motif (SEQ ID NO:69). In some embodiments, the transmembrane domain contains an AXXXA motif (SEQ ID NO: 77). In some embodiments, the transmembrane domain contains an AXXXS motif (SEQ ID NO: 78).

[0251] In some embodiments, the transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68). In some embodiments, the transmembrane domain comprises the motif LIxxGVxxGVxxT (SEQ ID NO: 70). In some embodiments, the transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68) and the motif LIxxGVxxGVxxT (SEQ ID NO: 70).

[0252] In some embodiments, the transmembrane domain is a transmembrane domain derived from Glycophorin A (GpA) or a variant thereof. In some embodiments, the transmembrane domain comprises a transmembrane domain derived from the transmembrane domain of Glycophorin A (GpA). In some embodiments, the transmembrane domain is a variant of the transmembrane domain of Glycophorin A (GpA). In some embodiments, the variant comprises one or more mutations, such as 1, 2, 3, 4, 5 or 6 mutations (e.g., amino acid substitutions), compared to a wild-type GpA transmembrane domain. In some embodiments, the one or more mutations promote alpha-helix dimerization. In some embodiments, the GpA transmembrane domain or the variant GpA30761-20002.40 transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68). In some embodiments, the GpA transmembrane domain or the variant GpA transmembrane domain comprises the motif LIxxGVxxGVxxT (SEQ ID NO: 70). In some embodiments, the GpA transmembrane domain or the variant GpA transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68) and the motif LIxxGVxxGVxxT (SEQ ID NO: 70).

[0253] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 22. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 22.

[0254] In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to30761-20002.40 SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain comprises the amino acid sequence to set forth in SEQ ID NO: 22. In some embodiments, the GpA transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 22.

[0255] In some embodiments, the transmembrane domain is a variant GpA transmembrane domain. In some embodiments, the transmembrane domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 43. In some embodiments, the transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 43.30761-20002.40

[0256] In some embodiments, the transmembrane domain comprises motif GXXXG (SEQ ID NO: 68) and GXXXA (SEQ ID NO: 69).

[0257] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from carnitine palmitoyltransferase 1 (CPT1). In some embodiments, the CPT1 transmembrane domain or a variant of the CPT1 transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68) and GXXXA (SEQ ID NO: 69).

[0258] In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 45. In some embodiments, the CPT1 transmembrane domain comprises the amino acid sequence set forth in SEQ30761-20002.40 ID NO: 45. In some embodiments, the CPT1 transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 45.

[0259] In some embodiments, the transmembrane domain promotes disulfide-linked dimerization. In some embodiments, the transmembrane domain comprises 1 to 6 cysteine residues. In some embodiments, the transmembrane domain comprises 1 cysteine residue. In some embodiments, the transmembrane domain comprises 2 cysteine residues. In some embodiments, the transmembrane domain comprises 3 cysteine residues. In some embodiments, the transmembrane domain comprises 4 cysteine residues. In some embodiments, the transmembrane domain comprises 5 cysteine residues. In some embodiments, the transmembrane domain comprises 6 cysteine residues. In some embodiments, the disulfide-linked dimerization comprises a disulfide bridge. In some embodiments, the disulfide- linked dimerization comprises 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization forms 1 disulfide bridge between polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide- linked dimerization forms 2 disulfide bridges between polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization forms 3 disulfide bridges between polypeptide chains of the synthetic cytokine receptor. In some embodiments, the disulfide-linked dimerization domain forms 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

[0260] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from interleukin 7 receptor (IL-7R). In some embodiments, the IL-7R transmembrane domain is a variant transmembrane domain. In some embodiments, the variant transmembrane domain comprises one or more mutations compared to a wild-type IL-7R transmembrane domain. In some embodiments, the one or more mutations promote homodimerization of the synthetic cytokine receptor. In some embodiments, the one or more mutations promote disulfide-linked dimerization. In some embodiments, the one or more mutations introduces at least one cysteine into the transmembrane domain. In some embodiments, one or more mutations introduces at least one proline into the transmembrane domain. In some embodiments, the mutation is, or comprises, the insertion or amino acid substitution of one or more cysteines, and / or one or more prolines. In some embodiments, the mutation is by introduction (e.g., insertion or amino acid substitution) of a trimer peptide of cysteine, proline, and another amino acid other than cystine or proline (e.g., threonine) into the IL-7R transmembrane domain. In some embodiments, the trimer peptide is a trimer peptide of cysteine, proline and threonine, such as in some cases a CPT insertion or a TCP insertion. In some embodiments, the transmembrane domain is a transmembrane domain from IL-7R or a portion thereof that comprises one or more mutations compared to a wild-type IL-7R transmembrane domain PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 71) or a contiguous sequence thereof of at least 21, 22, 23, 24, 25, 26, 27, or 28 amino acids. In some embodiments, the transmembrane domain also may contain 1, 2, 3 or 4 additional N-terminal or C-terminal amino acids compared to the sequence30761-20002.40 set froth in SEQ ID NO:71. In some embodiments, the transmembrane domain is a transmembrane domain from IL-7R or a portion thereof that comprises one or more mutations compared to a wild- type IL-7R transmembrane domain PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 71). In some embodiments, the variant transmembrane domain that contains one or more mutations compared to the wild-type IL-7R transmembrane domain has a sequence that is less than 100% identical to SEQ ID NO:71 and at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95% identical to SEQ ID NO: 71.

[0261] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 6. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 6.

[0262] In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a30761-20002.40 sequence of amino acids that is at least about 97% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 6. In some embodiments, the variant IL-7R transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 6.

[0263] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 7. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 7.

[0264] In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a30761-20002.40 sequence of amino acids that is at least about 97% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 7. In some embodiments, the variant IL-7R transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 7.

[0265] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 21. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 21.

[0266] In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 21. In some30761-20002.40 embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain comprises the amino acid sequence to set forth in SEQ ID NO: 21. In some embodiments, the variant IL-7R transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 21.

[0267] In some embodiments, the transmembrane domain is a transmembrane domain from a TNF receptor (TNFR), which naturally contain a transmembrane domain helix that can oligomerize, such as dimerize or trimerize. In some embodiments, the transmembrane domain derived from the TNFR is a transmembrane domain from TACI, Death Receptor 5 (DR5), p75NTR, Fas,TNFR1, TNFR2 or OX40. In some embodiments, inclusion of such transmembrane domains in provided synthetic cytokine receptors allows constitutive clustering of the intracellular domains that recruits and activates downstream signaling proteins such as JAKs and STATs. In some embodiments, the transmembrane domain contains a motif that supports oligomerization, such as dimerization and / or trimerization (see e.g., Zhao et al., 2020, Frontiers in Cell and Developmental Biology, 8.569684. 10.3389 / fcell.2020.569684), incorporated by reference herein). In some embodiments, the transmembrane domain derived from a TNFR contains a proline rich motif ĭPXĭ (SEQ ID NO: 75), in which ĭ represents a hydrophobic residue, P is proline and X can be any amino acid, typically an apolar residue except for proline and glycine. In some embodiments, the transmembrane domain derived from a TNFR contains a ĭTXXAĭ, in which ĭ represents a hydrophobic residue, T is threonine, X can be any amino acid, typically an apolar residue except for proline and glycine, and A is alanine. In some embodiments, the transmembrane domain derived from a TNFR contains a GXXXG motif (SEQ ID NO:68). In some embodiments, the transmembrane domain derived from a TNFR contains a GXXXA motif (SEQ ID NO:69). In some embodiments, the transmembrane domain derived from a TNFR contains an AXXXA motif (SEQ ID NO: 77). In some embodiments, the transmembrane domain derived from a TNFR contains an AXXXS motif (SEQ ID NO: 78).

[0268] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from DR5. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain30761-20002.40 comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 46. In some embodiments, the DR5 transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 46. In some embodiments, any of such DR5 transmembrane domain comprises the motif ĭTXXAĭ (SEQ ID NO: 76) and / or the motif GXXXG (SEQ ID NO:68). In some embodiments, any of such DR5 transmembrane domain comprises the motif ĭTXXAĭ (SEQ ID NO: 76). In some embodiments, any of such DR5 transmembrane domain comprises the motif GXXXG (SEQ ID NO:68). In some embodiments, any of such DR5 transmembrane domain comprises the motif ĭTXXAĭ (SEQ ID NO: 76) and the motif GXXXG (SEQ ID NO:68).

[0269] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from TACI. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 44. In some30761-20002.40 embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, the TACI transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, any of such TACI transmembrane domain comprises the motif AXXXS (SEQ ID NO:78).

[0270] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Muc24.

[0271] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 23. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 23.

[0272] In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 23. In some embodiments, the Muc2430761-20002.40 transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain comprises the amino acid sequence to set forth in SEQ ID NO: 23. In some embodiments, the Muc24 transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 23.

[0273] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from Thrombopoietin Receptor (TpoR). In some embodiments, the TpoR transmembrane domain is a variant transmembrane domain. In some embodiments, the variant transmembrane domain comprises one or more mutations compared to a wild-type TpoR transmembrane domain (ISLVTALHLVLGLSAVLGLLLL; SEQ ID NO: 169). In some embodiments, the one or more mutations promote homodimerization of the synthetic cytokine receptor. In some embodiments, the one or more mutations promote alpha-helix dimerization. In some embodiments, the variant transmembrane domain that contains one or more mutations compared to the wild-type TpoR transmembrane domain has a sequence that is less than 100% identical to SEQ ID NO: 169 and at30761-20002.40 least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 169. In some embodiments, the one or more mutations replaces at least one amino acid residue in the wild-type transmembrane domain with a leucine residue. In some embodiments, the one or more mutations replaces at least one amino acid residue in the wild-type transmembrane domain with an asparagine residue. In some embodiments, the one or more mutations replaces one or more amino acid residues in the wild-type transmembrane domain with a leucine residue and an asparagine residue. In some embodiments, the TpoR TMD comprises amino acid substitution H499L with reference to wild-type TpoR (SEQ ID NO: 168) or H8L with reference to wild-type TpoR transmembrane domain (SEQ ID NO: 169). In some embodiments, the TpoR TMD comprises amino acid substitution S505N with reference to wild-type TpoR or S14N with reference to wild-type TpoR transmembrane domain . In some embodiments, the TpoR TMD comprises amino acid substitution H499L and S505N with reference to wild-type TpoR or H8L and S14N with reference to wild-type TpoR transmembrane domain.

[0274] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 169. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 169.

[0275] In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to30761-20002.40 SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain comprises the amino acid sequence to set forth in SEQ ID NO: 169. In some embodiments, the TpoR transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 169.

[0276] In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 163. In some embodiments, the transmembrane domain comprises an amino acid sequence of SEQ ID NO: 163.

[0277] In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 163. In some embodiments, the TpoR30761-20002.40 transmembrane domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain comprises the amino acid sequence to set forth in SEQ ID NO: 163. In some embodiments, the TpoR transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 163.

[0278] In some embodiments, the transmembrane domain comprises a transmembrane domain derived from wild-type IL-9R. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 125. In some embodiments, the wild-type IL-9R transmembrane domain comprises the amino acid sequence to set forth in SEQ ID NO: 125. In some embodiments, the wild- type IL-9R transmembrane domain consists of the amino acid sequence set forth in SEQ ID NO: 125.

[0279] In some embodiments, the transmembrane domain provided herein can comprise any one of the transmembrane domains set forth in Table 2. As indicated, the exact locus or residues corresponding to a given domain can vary, such as depending on the methods used to identify or classify the domain. Also, in some cases, adjacent N- and / or C-terminal amino acids of a given transmembrane domain also can be included in a sequence of a synthetic cytokine receptor, so long as the resulting receptor is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules. Thus, it is understood that the exemplification of the SEQ ID NOS in Table 2 is not to be construed as limiting. For example, the particular transmembrane domain can be several amino acids longer or shorter, such as 1-10, e.g., 1, 2, 3, 4, 5, 6 or 7 amino acids longer or shorter, than the sequence of amino acids set forth in the respective SEQ ID NO. Also provided are variants of any such SEQ ID NO (e.g., sequence that exhibits at least about 90% identity, at least about 91% identity, at least about 92% identity, at least about 93% identity, at least about 94% identity, at least about 95% identity, such as at least about 96% identity, 97% identity, 98% identity, or 99% identity to any one of SEQ ID NOS: 6, 7, 21, 22, 23, 43, 44, 45, 46, 125, 163 or 169), in which the resulting synthetic cytokine receptor containing such a variant transmembrane domain is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules.30761-20002.40C. Intracellular Domain

[0280] Provided embodiments relate to a synthetic cytokine receptor that comprises an extracellular domain (e.g., any as described in Section II.A), a transmembrane domain (e.g., any as described in Section II.B), and an intracellular domain capable of interleukin 9 receptor (IL-9R) signaling. In some embodiments, the intracellular domain comprises an IL-9R intracellular domain or a variant thereof. In some embodiments, the intracellular domain comprises a chimeric JAK / STAT fusion domain. 1. IL-9R intracellular domain or Variant Thereof

[0281] In some embodiments, the intracellular domain comprises the intracellular domain of a naturally occurring IL-9R (e.g., set forth in SEQ ID NO:8). In some embodiments, the intracellular domain comprises one or more mutations compared to a naturally occurring IL-9R (e.g., one or more mutations compared to the sequence set forth in SEQ ID NO:8). The one or more mutation(s) may be a substitution, insertion, deletion, or combination thereof. In some embodiments, the one or more mutation(s) promote downstream signaling. Methods of determining whether a particular mutation will trigger the downstream signaling is known to a skilled artisan (e.g., assaying for STAT1, STAT3, or STAT5 phosphorylation following growth of the cells harboring the receptor being tested in the absence of growth factors).

[0282] In some embodiments, the intracellular domain is at least about 150 amino acids in length. In some embodiments, the intracellular domain is at most about 250 amino acids in length. In some embodiments, the intracellular domain is about 150 amino acids to about 250 amino acids in length. In some embodiments, the intracellular domain is about 169, 220, 223, or 230 amino acids in length. In some embodiments, the intracellular domain is about 169 amino acids in length. In some embodiments, the intracellular domain is about 220 amino acids in length. In some embodiments, the intracellular domain is about 223 amino acids in length. In some embodiments, the intracellular30761-20002.40 domain is about 230 amino acids in length. In some embodiments, the intracellular domain is 169 amino acids in length. In some embodiments, the intracellular domain is 220 amino acids in length. In some embodiments, the intracellular domain is 223 amino acids in length. In some embodiments, the intracellular domain is 230 amino acids in length.

[0283] In some embodiments, the IL-9R intracellular domain is wild-type IL-9R intracellular domain or is a variant thereof that comprises one or more mutations compared to the wild-type IL-9R intracellular domain set forth in SEQ ID NO: 8. In some embodiments, the one or more mutations comprise one or more amino acid insertions, deletions, and / or substitutions. In some embodiments, the one or more mutations promote signaling through STAT1, STAT3, and / or STAT5 pathways.

[0284] In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX1 motif and / or a BOX2 motif. In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX2 motif.

[0285] In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX 1 motif, which is defined as proline, any amino acid residue, and proline preceded by hydrophobic sequences. In some embodiments, the IL-9R intracellular domain, including a variant IL- 9R intracellular domain, contains the proline rich BOX1 motif that allows JAK molecules to bind. In some embodiments, the BOX1 motif is the sequence FYQNVPSPA (SEQ ID NO:79; corresponding to positions 10-18 of the sequence set forth in SEQ ID NO:8).

[0286] In some embodiments, the IL-9R intracellular domain or variant thereof comprises a BOX 2 motif, which is defined as a cluster of hydrophobic amino acids followed by positively charged amino acids. In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains the BOX2 motif that allows STAT molecules to bind.

[0287] In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains a conserved tyrosine residue at the position corresponding to position 116 in the sequence set forth in SEQ ID NO:8. In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, additionally contains a conserved proline at position 118 and a conserved glutamine at position 119, each with reference to positions corresponding to positions set forth in SEQ ID NO:8. In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains a conserved glutamine residue at the position corresponding to position 118 in the sequence set forth in SEQ ID NO: 8.

[0288] In some embodiments, the IL-9R intracellular domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 8.

[0289] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 8. In some embodiments, the IL-9R30761-20002.40 intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 8.

[0290] In some embodiments, the IL-9R intracellular domain comprises deletion of contiguous amino acids compared to wild-type IL-9R intracellular domain. In some embodiments, the mutation is a deletion and the variant is a deleted IL-9R intracellular signaling domain lacking one or more regions of the wild-type IL-9R intracellular signaling domain (e.g., lacking one or more regions of the sequence set forth in SEQ ID NO:8). In some embodiments, the IL-9R lacks up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 contiguous amino acids present within a wild-type IL- 9R intracellular domain (e.g., SEQ ID NO:8). In some embodiments, the IL-9R lacks a region of 10 contiguous amino acids with reference to a wild-type IL-9R intracellular domain. In some30761-20002.40 embodiments, the region that is deleted is a sequence that is not necessary for functional activity of the IL-9R intracellular domain such that IL-9R-mediated signaling is retained.

[0291] In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains deletion of amino acids NGNFQTWMGA (SEQ ID NO:82; corresponding to deletion of amino acids 29-38 with reference to positions set forth in SEQ ID NO:8). In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains deletion of amino acids HGAGVLLSQD (SEQ ID NO:81; corresponding to deletion of amino acids 39-48 with reference to positions set forth in SEQ ID NO:8). In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains deletion of amino acids TCGPARPWKS (SEQ ID NO:83; corresponding to deletion of amino acids 69-78 with reference to positions set forth in SEQ ID NO: 8). In some embodiments, the IL-9R intracellular domain, including a variant IL-9R intracellular domain, contains deletion of amino acids ALGCYGGWHL (SEQ ID NO: 80; corresponding to deletion of amino acids 154-163 with reference to positions set forth in SEQ ID NO: 8). In some embodiments, one or more additional mutation can be present in any of such truncated IL-9R intracellular domain.

[0292] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least30761-20002.40 about 94% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 51. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 51.

[0293] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain30761-20002.40 comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 52.

[0294] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 53. In some30761-20002.40 embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 53.

[0295] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 54.30761-20002.40

[0296] In some embodiments, the mutation is a deletion and the variant is a truncated IL-9R intracellular signaling domain that is truncated by deletion of one or more amino acid residues at one or both of the N- and C-terminus of a wild-type IL-9R intracellular domain. In some embodiments, the truncated IL-9R is a contiguous sequence of amino acids of at least 150 amino acids in length from the wild-type IL-9R intracellular signaling domain set forth in SEQ ID NO:8 that is truncated by deletion of one or more amino acid residues at one or both of the N- and C-terminus of SEQ ID NO:8. In some embodiments, the truncated IL-9R signaling domain is a contiguous sequence of from 150 amino acids to 229 amino acids of the sequence set forth in SEQ ID NO:8. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 80 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 70 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to680 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 50 amino acids. In some embodiments, the variant IL-9R is an N- terminal truncation of up to 40 amino acids. In some embodiments, the variant IL-9R is an N- terminal truncation of up to 30 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 20 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 10 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 7 amino acids. In some embodiments, the variant IL-9R is an N-terminal truncation of up to 5 amino acids. In some embodiments, one or more additional mutation can be present in any of such truncated IL-9R intracellular domain.

[0297] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 55. In some30761-20002.40 embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 94% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 55. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 55.

[0298] In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that exhibits at least about 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 75% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 80% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 85% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 86% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 87% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 88% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 89% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 90% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 91% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 92% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 93% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least30761-20002.40 about 94% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 95% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 96% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 97% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 98% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises a sequence of amino acids that is at least about 99% identical to SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 56. In some embodiments, the IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 56.Exemplary of any of such intracellular domains, including wild-type or variant IL-9R intracellular domains or chimeric JAK / STAT fusion intracellular domains are described in the subsections that follow below.

[0299] In some embodiments, the intracellular domain provided herein can comprise any one of the intracellular domains set forth in Table 3. In some cases, adjacent N- and / or C-terminal amino acids of a given intracellular domain also can be included or deleted in a sequence of a synthetic cytokine receptor, so long as the resulting receptor is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules. Thus, it is understood that the exemplification of the SEQ ID NOS in Table 3 is not to be construed as limiting. For example, the particular intracellular domain can be several amino acids longer or shorter, such as 1-10, e.g., 1, 2, 3, 4, 5, 6 or 7 amino acids longer or shorter, than the sequence of amino acids set forth in the respective SEQ ID NO. Also provided are variants of any such SEQ ID NO (e.g., sequence that exhibits at least about 90% identity, at least about 91% identity, at least about 92% identity, at least about 93% identity, at least about 94% identity, at least about 95% identity, such as at least about 96% identity, 97% identity, 98% identity, or 99% identity to any one of SEQ ID NOS: 8 or 51-56), in which the resulting synthetic cytokine receptor containing such a variant IL-9R intracellular domain is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules.a. Wild-type IL-9R Intracellular Domain (ICD)

[0300] In some embodiments, the intracellular domain is capable of interleukin 9 receptor (IL- 9R) signaling. In some embodiments, the intracellular domain capable of IL-9R signaling comprises30761-20002.40 an intracellular domain of IL-9R. In some embodiments, the IL-9R intracellular domain comprises a naturally occurring IL-9R (i.e., wild-type IL-9R). In some embodiments, the IL-9R intracellular domain comprises a mammalian IL-9R. In some embodiments, the IL-9R intracellular domain comprises a human IL-9R. In some embodiments, the IL-9R intracellular domain comprises a wild- type human IL-9R.

[0301] In some embodiments, the IL-9R intracellular domain is 230 amino acids in length. In some embodiments, the wild-type IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 8. In some embodiments, the wild-type IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the wild-type IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 8. b. Variant IL-9R Intracellular Domain (ICD)

[0302] In some embodiments, the intracellular domain is a variant IL-9R intracellular domain capable of interleukin 9 receptor (IL-9R) signaling. In some embodiments, the variant IL-9R intracellular domain comprises one or more mutations compared to a naturally occurring IL-9R. The one or more mutation(s) may be a substitution, insertion, deletion, or combination thereof. In some embodiments, the one or more mutation(s) promote downstream signaling. Methods of determining whether a particular mutation will trigger the downstream signaling is known to a skilled artisan (e.g., assaying for STAT1, STAT3, or STAT5 phosphorylation following growth of the cells harboring the receptor being tested in the absence of growth factors). In some embodiments, the variant IL-9R intracellular domain elicits signaling through STAT1, STAT3, and / or STAT5 pathways.

[0303] In some embodiments, STAT1 signaling by variant IL-9R is increased compared to STAT1 signaling by wild-type IL-9R. In some embodiments, STAT3 signaling by variant IL-9R is increased compared to STAT3 signaling by wild-type IL-9R. In some embodiments, STAT5 signaling by variant IL-9R is increased compared to STAT5 signaling by wild-type IL-9R. In some embodiments, signaling through the STAT1, STAT3, and / or STAT5 pathways is sustained for a longer period of time compared to STAT1, STAT3, and / or STAT5 via wild-type IL-9R. In some embodiments, the period of time is about 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or longer. In some embodiments, the period of time is about 24 hours. In some embodiments, signaling through STAT1, STAT3, and / or STAT5 is sustained for as long as the cell expresses any of the synthetic cytokine receptors provided herein. In some embodiments, sustained STAT1, STAT3, and / or STAT5 signaling is determined by phosphorylation status of STAT1, STAT3, and / or STAT5.

[0304] In some embodiments, the IL-9R intracellular domain comprises deletions of a region such as those outlined in Table 4. In some embodiments, the IL-9R intracellular domain comprises deletions of contiguous amino acids compared to wild-type IL-9R intracellular domain. In some30761-20002.40 embodiments, the IL-9R intracellular domain comprises a deletion of a region, such as those outlined in Table 4, at the C terminus of wild-type IL-9R intracellular domain. In some embodiments, the IL- 9R intracellular domain comprises a deletion of a region at the N terminus of wild-type IL-9R intracellular domain. In some embodiments, the IL-9R intracellular domain comprises a deletion of a region of contiguous amino acids within the wild-type IL-9R intracellular domain. In some embodiments, the IL-9R intracellular domain comprises deletions of non-contiguous amino acids compared to the wild-type IL-9R intracellular domain. In some embodiments, the IL-9R intracellular domain comprises deletions of a plurality of regions, such as those outlined in Table 4, of the wildtype IL-9R intracellular domain. Exemplary deleted regions from IL-9R intracellular domain are shown in Table 4A. Table 4A: Exemplary Deletion Mutations

[0305] Exemplary deleted regions from the IL-9R intracellular domain are shown in Table 4B. In some embodiments, the IL-9R intracellular domain is deleted for contiguous amino acids within or including contiguous amino acids 29-38, 39-48, 69-78 or 154-163, with reference to numbering of amino acids in SEQ ID NO:8, or any combination thereof. Table 4B: Exemplary Deleted Regions30761-20002.40

[0306] In some embodiments, the IL-9R intracellular domain comprises deletions of a plurality of regions, of the wildtype IL-9R intracellular domain. Exemplary intracellular domains with a plurality of deleted regions from IL-9R intracellular domain are shown in Table 4C. Table 4C: Exemplary Deletions of Multiple Regions

[0307] In some embodiments, the variant IL-9R intracellular domain is a truncated IL-9R that lacks a contiguous sequence of amino acids between the N-terminus and C-terminus of wild-type IL- 9R intracellular domain. In some embodiments, the variant IL-9R intracellular domain is a truncated IL-9R that lacks a noncontiguous sequence of amino acids between the N-terminus and C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the variant IL-9R intracellular domain is a truncated IL-9R that lacks a contiguous sequence of amino acids at the C-terminus of wild-type IL-30761-20002.40 9R intracellular domain. In some embodiments, the variant IL-9R intracellular domain is a truncated IL-9R that lacks a contiguous sequence of amino acids at the N-terminus of wild-type IL-9R intracellular domain. In some embodiments, the variant IL-9R intracellular domain is a truncated IL- 9R that lacks a noncontiguous sequence of amino acids at the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the variant IL-9R intracellular domain is a truncated IL- 9R that lacks a noncontiguous sequence of amino acids at the N-terminus of wild-type IL-9R intracellular domain. In some of any of such embodiments, the truncation is at the C-terminus of wild-type IL-9R intracellular domain set forth in SEQ ID NO: 8. In some of any of such embodiments, the truncation is at the N-terminus of wild-type IL-9R intracellular domain set forth in SEQ ID NO: 8.

[0308] In some embodiments, the truncated IL-9R intracellular domain or variant thereof is truncated by between 62 and 99 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the truncated IL-9R intracellular domain or variant thereof is truncated by 61 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the truncated IL-9R intracellular domain or variant thereof is truncated by 62 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain. In some embodiments, the truncated IL-9R intracellular domain or variant thereof is truncated by 99 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain.

[0309] In some embodiments, the variant IL-9R intracellular domain is a truncated IL-9R that lacks amino acids 132 to 230 of SEQ ID NO:8. In some embodiments, the variant IL-9R intracellular domain lacks amino acids 134 to 230 of SEQ ID NO:8.

[0310] In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 84. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 84. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 84. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 85. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 85. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 51. In some embodiments, the variant30761-20002.40 IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 51. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 51. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 52. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 52. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 86. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 87. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 87. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 87. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 53. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 53. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 88. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 89. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 89. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 89. In some embodiments, the variant IL-9R intracellular domain comprises a sequence30761-20002.40 of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 90. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 91. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 92. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 93. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 93. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 93. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 94. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 94. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 94. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 54. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 54. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 95. In some embodiments, the variant IL-9R intracellular domain comprises30761-20002.40 the amino acid sequence set forth in SEQ ID NO: 95. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 95. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 96. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 96. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 97. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 97. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 97. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 98. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 98. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 98. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 99. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 99. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 99. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 100. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 100. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 55. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 55. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 55. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at30761-20002.40 least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 56. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 56. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 56. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 103. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 103. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 103. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 104. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 104. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 104.

[0311] In some embodiments, the variant IL-9R intracellular domain comprises one or more amino acid deletions and insertions. In some embodiments, the IL-9R intracellular domain comprises deletion of a contiguous sequence of amino acids and insertion of a contiguous sequence of amino acids. In some embodiments, the length of the deleted contiguous sequence of amino acids and length of the inserted contiguous sequence of amino acids are the same. In some embodiments, the length of the deleted contiguous sequence of amino acids and length of the inserted contiguous sequence of amino acids are the different.

[0312] In some embodiments, the variant IL-9R intracellular domain comprises replacement of a contiguous sequence of amino acids with one or more STAT binding domains. In some embodiments, the contiguous sequence of amino acids is replaced with one STAT binding domain. In some embodiments, the STAT binding domain is derived from a Type I cytokine receptor. In some embodiments, the Type I cytokine receptor is selected from the group consisting of interleukin 2 receptor (IL-2R), interleukin 4 receptor (IL-4R), interleukin 7 receptor (IL-7R), interleukin 13 receptor (IL-13R), interleukin 15 receptor (IL-15R), and interleukin 2 receptor (IL-21R). In some embodiments, the Type I cytokine receptor is IL-2R.

[0313] In some embodiments, the contiguous sequence of amino acids is replaced with one or more STAT binding domains. In some embodiments, the contiguous sequence of amino acids is replaced with one STAT binding domain. In some embodiments, the contiguous sequence of amino acids is replaced with two STAT binding domains. In some embodiments, the contiguous sequence of amino acids is replaced with three STAT binding domains. In some embodiments, the contiguous sequence of amino acids is replaced with four STAT binding domains. In some embodiments, the30761-20002.40 contiguous sequence of amino acids is replaced with five STAT binding domains. In some embodiments, replacement of the contiguous sequence of amino acids with one, two, three, four or five STAT binding domains increases STAT binding and signaling.

[0314] In some embodiments, the variant IL-9R intracellular domain comprises one or more YLPQ, YRPQ, YLPL, or YLKQ STAT binding domains. In some embodiments, the variant IL-9R intracellular domain comprises two or more YLPQ, YRPQ, YLPL, or YLKQ STAT binding domains. In some embodiments, the variant IL-9R intracellular domain comprises three or more YLPQ, YRPQ, YLPL, or YLKQ STAT binding domains. In some embodiments, the variant IL-9R intracellular domain comprises four or more YLPQ, YRPQ, YLPL, or YLKQ STAT binding domains. In some embodiments, the variant IL-9R intracellular domain comprises five or more YLPQ, YRPQ, YLPL, or YLKQ STAT binding domains.

[0315] In some embodiments, the one or more STAT binding domains comprises YLPQ (SEQ ID NO: 171). In some embodiments, the one or more STAT binding domains comprises YRPQ (SEQ ID NO: 172). In some embodiments, the one or more STAT binding domains comprises YLPL (SEQ ID NO: 173). In some embodiments, the one or more STAT binding domain comprises YLKQ (SEQ ID NO: 174).In some embodiments, the STAT binding domain comprises a STAT1 binding domain. In some embodiments, the STAT binding domain comprises a STAT3 binding domain. In some embodiments, the STAT binding domain comprises a STAT5 binding domain.

[0316] In some embodiments, the STAT5 binding domain is 11 amino acids in length. In some embodiments, the STAT5 binding domain comprises amino acid sequence LNTDAYLSLQE (SEQ ID NO: 120). In some embodiments, the contiguous sequence of amino acids that is replaced with the one or more STAT binding domains comprises 11 amino acid residues. In some embodiments, the contiguous sequence of amino acids that is replaced with the one or more STAT binding domains comprises SNNNNYCALGC (SEQ ID NO: 170). Exemplary insertion mutations of one, two, and three STAT binding domains are shown in Table 5. Table 5: Exemplary Insertion Mutations

[0317] In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 110. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 110. In some embodiments, the variant30761-20002.40 IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 110. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 111. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 111. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 111. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 112. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 112. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 112.

[0318] In some embodiments, the variant IL-9R intracellular domain comprises one or more amino acid substitutions with reference to wild-type IL-9R intracellular domain (SEQ ID NO:8). In some embodiments, the variant IL9R intracellular domain comprises a STAT binding motif. In some embodiments, the one or more amino acid substitutions are located in the STAT binding motif of the IL-9R intracellular domain. In some embodiments, the STAT binding motif comprises a STAT1, STAT3, and / or STAT5 binding motif.

[0319] In some embodiments, the STAT binding motif comprises YLPQ (SEQ ID NO: 171). In some embodiments, the STAT binding motif comprises a variant STAT binding motif. In some embodiments, the variant STAT binding motif comprises one or more amino acid substitutions with reference to SEQ ID NO: 171. In some embodiments, the amino acid substitution comprises substitution of a leucine residue for an arginine residue with reference to SEQ ID NO: 171. In some embodiments, the amino acid substitution comprises substitution of a glutamine residue for a leucine residue with reference to SEQ ID NO: 171. In some embodiments, the amino acid substitution comprises substitution of a proline with a lysine with reference to SEQ ID NO: 171.

[0320] In some embodiments, the STAT binding motif comprises YRPQ (SEQ ID NO: 172). In some embodiments, the STAT binding motif comprises YLPL (SEQ ID NO: 173). In some embodiments, the STAT binding motif comprises YLKQ (SEQ ID NO: 174).

[0321] In some embodiments, STAT1, STAT3, and / or STAT5 bind YLPQ. In some embodiments, STAT1, STAT3, and STAT5 bind YLPQ. In some embodiments, STAT1 and / or STAT3 bind YRPQ. In some embodiments, STAT1 and STAT3 bind YRPQ. In some embodiments, STAT5 binds YLPL. In some embodiments, STAT1, STAT3, and / or STAT5 bind YLKQ. In some embodiments, STAT1, STAT3, and STAT5 bind YLKQ.

[0322] In some embodiments, the one or more amino acid substitutions of the STAT binding motif with reference to SEQ ID NO: 171 (YLPQ) are shown Table 6.30761-20002.40 Table 6: Exemplary Substitution Mutations

[0323] In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 107. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 107. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 107. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 108. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 108. In some embodiments, the variant IL-9R intracellular domain comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 109. In some embodiments, the variant IL-9R intracellular domain comprises the amino acid sequence set forth in SEQ ID NO: 109. In some embodiments, the variant IL-9R intracellular domain consists of the amino acid sequence set forth in SEQ ID NO: 109. In some embodiments, the variant IL-9R intracellular domain provided herein can comprise any one of the variant IL-9R intracellular domains set forth in Table 7. In some embodiments, the variant IL-9R intracellular domain can comprise any combination of the variant IL- 9R intracellular domains set forth in Table 7. In some embodiments, the variant IL-9R intracellular domain comprises one or more amino acid deletions with reference to a wild-type IL-9R intracellular domain and one or more amino acid substitutions with reference to a wild-type IL-9R intracellular domain. In some embodiments, the variant IL-9R intracellular domain comprises one or more amino acid deletions with reference to a wild-type IL-9R intracellular domain and one or more amino acid insertions with reference to a wild-type IL-9R intracellular domain.

[0324] In particular embodiments, the variant IL-9R intracellular domain comprises IL9R(Large D2) (SEQ ID NO: 103), IL9R(Large D2’) (SEQ ID NO: 104) or IL9R(d15) (SEQ ID NO: 54) and one30761-20002.40 or amino acid substitutions as represented by IL9R(Mut6YRPQ) (SEQ ID NO: 107), IL9R(Mut7YLPL) (SEQ ID NO: 108), or IL9R(Mut9YLKQ) (SEQ ID NO: 109).2. Chimeric JAK / STAT Fusion Intracellular Domain (ICD)

[0325] In some embodiments, the intracellular domain is a chimeric fusion domain capable of interleukin 9 receptor (IL-9R) signaling. In some embodiments, the chimeric fusion domain comprises a JAK binding domain derived from IL-7R fused to a STAT binding domain derived from IL-9R. In Some embodiments, the chimeric fusion domain comprises a JAK binding domain derived from TpoR fused to a STAT binding domain derived from IL-9R.

[0326] In some embodiments, the chimeric JAK / STAT fusion domain promotes downstream signaling. Methods of determining whether the chimeric JAK / STAT fusion domain will trigger the downstream signaling is known to a skilled artisan (e.g., assaying for STAT1, STAT3, or STAT5 phosphorylation following growth of the cells harboring the receptor being tested in the absence of growth factors). In some embodiments, the chimeric JAK / STAT fusion domain elicits signaling through STAT1, STAT3, and / or STAT5 pathways.

[0327] In some embodiments, STAT1 signaling by the chimeric JAK / STAT fusion domain is increased compared to STAT1 signaling by wild-type IL-9R. In some embodiments, STAT3 signaling by the chimeric JAK / STAT fusion domain is increased compared to STAT3 signaling by wild-type IL-9R. In some embodiments, STAT5 signaling by the chimeric JAK / STAT fusion domain is increased compared to STAT5 signaling by wild-type IL-9R. In some embodiments, STAT1, STAT3, and / or STAT5 signaling is sustained for a longer period of time by the chimeric JAK / STAT fusion domain compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R. In some embodiments, the period of time is about 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, or 72 hours. In some embodiments, the period of time is about 24 hours. In some embodiments, sustained STAT1, STAT3, and / or STAT5 signaling is determined by phosphorylation status of STAT1, STAT3, and / or STAT5.

[0328] In some embodiments, the chimeric JAK / STAT fusion domain comprises a JAK binding domain from a type I cytokine receptor and a STAT binding domain from an IL-9R intracellular domain.

[0329] In some embodiments, the IL-9R STAT binding domain comprises amino acid residues 73 to 230 of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is 59 to 158 amino acids in length and comprises an IL-9R STAT binding motif. In some embodiments, the IL-9R30761-20002.40 STAT binding motif comprises YLPQ (SEQ ID NO: 171). In some embodiments, the IL-9R STAT binding domain comprises one or more amino acid deletions with reference to the IL-9R ICD set forth in SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the N-terminus of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the C-terminus of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 1 to 72 of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 132 to 230 of SEQ ID NO: 8. In some embodiments, the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 1 to 72 and 132 to 230 of SEQ ID NO: 8. Exemplary STAT binding domains from a IL-9R receptors are shown in Table 8. Table 8: Exemplary JAK binding domains

[0330] In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 122. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence of SEQ ID NO: 122. In some embodiments, the IL-9R STAT binding domain consists of the amino acid sequence set forth in SEQ ID NO: 122. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 123. In some embodiments, the IL-9R STAT binding domain comprises an amino acid sequence of SEQ ID NO: 123. In some embodiments, the IL-9R STAT binding domain consists of the amino acid sequence set forth in SEQ ID NO: 123.

[0331] In some embodiments, the type I cytokine receptor is selected from the group consisting of interleukin 2 receptor (IL-2R), interleukin 4 receptor (IL-4R), interleukin 7 receptor (IL-7R), interleukin 13 receptor (IL-13R), interleukin 15 receptor (IL-15R), interleukin 2 receptor (IL-21R), and thrombopoietin receptor (TpoR). In some embodiments, the type I cytokine receptor is IL-7R. In some embodiments, the type I cytokine receptor is TpoR. Exemplary JAK binding domains from a type I cytokine receptors are shown in Table 9. Table 9: Exemplary JAK binding domains30761-20002.40

[0332] In some embodiments, the IL-7R JAK binding domain is up to 65 amino acids in length. In some embodiments, the IL-7R JAK binding domain is 65 amino acids in length. In some embodiments, the IL-7R JAK binding domain comprises a box 1 motif. In some embodiments, the IL- 7R JAK binding domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 119. In some embodiments, the IL-7R JAK binding domain comprises an amino acid sequence of SEQ ID NO: 119. In some embodiments, the IL-7R JAK binding domain consists of the amino acid sequence set forth in SEQ ID NO: 119. In some embodiments, the IL-7R JAK binding domain comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 121. In some embodiments, the IL-7R JAK binding domain comprises an amino acid sequence of SEQ ID NO: 121. In some embodiments, the IL-7R JAK binding domain consists of the amino acid sequence set forth in SEQ ID NO: 121.

[0333] In some embodiments, the chimeric JAK / STAT fusion intracellular domain comprises a fusion of any of the JAK and STAT binding domains described above. In some embodiments, the chimeric JAK / STAT fusion intracellular domain comprises about 223 amino acids. In some embodiments, the JAK / STAT fusion intracellular domain is a truncated version of the 223 amino acid sequence. In some embodiments, the JAK / STAT fusion intracellular domain is truncated at the C terminus. In some embodiments, 99 amino acids are truncated from the C terminus. In other embodiments, 97 amino acids are truncated from the C terminus. In some embodiments, the chimeric JAK / STAT fusion intracellular domain provided herein can comprise any one of the intracellular domains set forth in Table 10.

[0334] In some embodiments, the chimeric JAK / STAT fusion comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 114. In some embodiments, the chimeric JAK / STAT fusion comprises the amino acid30761-20002.40 sequence set forth in SEQ ID NO: 114. In some embodiments, the chimeric JAK / STAT fusion consists of the amino acid sequence set forth in SEQ ID NO: 114. In some embodiments, the chimeric JAK / STAT fusion comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 116. In some embodiments, the chimeric JAK / STAT fusion comprises the amino acid sequence set forth in SEQ ID NO: 116. In some embodiments, the chimeric JAK / STAT fusion consists of the amino acid sequence set forth in SEQ ID NO: 116. In some embodiments, the TpoR JAK binding domain comprises a variant TpoR JAK binding domain. In some embodiments, the variant TpoR JAK binding domain comprises one or more mutations compared to a wild-type TpoR JAK binding domain set forth in SEQ ID NO: 177 (RKQFPAHYRRLRHALWPSLPDLHRVLGQYLRDTAALSPPKATVSDTCEEVEPSLLEILPKSSE RTPLPL). In some embodiments, the one or more mutations promote homodimerization of the synthetic cytokine receptor. In some embodiments, the one or more mutations promote alpha-helix dimerization. In some embodiments, the one or more mutations replaces at least one amino acid residue in the wild-type TpoR JAK binding domain with an arginine residue. In some embodiments, the TpoR JAK binding domain is up to 70 amino acids in length. In some embodiments, the TpoR JAK binding domain is 69 amino acids in length. In some embodiments, the TpoR JAK binding domain comprises a box 1 motif. In some embodiments, the TpoR JAK binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 175. In some embodiments, the TpoR JAK binding domain comprises an amino acid sequence of SEQ ID NO: 175. In some embodiments, the TpoR JAK binding domain consists of the amino acid sequence set forth in SEQ ID NO: 175. In some embodiments, the box 1 motif comprises an amino acid sequence of LWPSLPDLH (SEQ ID NO: 176). D. Variants of Synthetic Cytokine Receptors

[0335] Amino acid sequence modification(s) of the synthetic cytokine receptors provided herein are contemplated. For example, it may be desirable to improve the signaling elicited by the synthetic cytokine receptors; it may also be desirable to improve other biological properties of the synthetic cytokine receptors, including but not limited to thermostability, expression level, or solubility. Thus, in addition to the synthetic cytokine receptors described herein, it is contemplated that variants can be prepared.

[0336] In some embodiments, the synthetic cytokine receptors provided herein are chemically modified, for example, by the covalent attachment of any type of molecule to the synthetic cytokine receptors. Exemplary non-limiting modifications include glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Additionally, the synthetic cytokine receptors may contain one or more non-classical amino acids.30761-20002.40

[0337] In some embodiments, variations may be a substitution, deletion, or insertion of one or more codons encoding the synthetic cytokine receptors that results in a change in the amino acid sequence as compared with the original sequence.

[0338] Amino acid substitutions can be the result of replacing one amino acid with another amino acid having similar structural and / or chemical properties, such as the replacement of a leucine with a serine, e.g., conservative amino acid replacements. Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a molecule provided herein, including, for example, site-directed mutagenesis and PCR-mediated mutagenesis which results in amino acid substitutions.

[0339] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Families of amino acid residues having side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains ( e.g., aspartic acid, glutamic acid), uncharged polar side chains ( e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g, tyrosine, phenylalanine, tryptophan, histidine). Naturally occurring residues may be divided into groups based on common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, lie; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe. Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed and the activity of the protein can be determined.

[0340] Substantial modifications in the biological properties of the synthetic cytokine receptor are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.

[0341] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from 1 residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues.

[0342] Amino acid sequence deletions include amino- and / or carboxyl-terminal deletions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence deletions of single or multiple amino acid residues. E. Exemplary Synthetic Cytokine Receptors30761-20002.40

[0343] In some embodiments, the synthetic cytokine receptor provided herein can comprise any one of the extracellular, transmembrane, and intracellular domains provided herein. In some embodiments, the synthetic cytokine receptor provided herein can comprise one extracellular domain from Table 1, one transmembrane domain from Table 2, and one intracellular domain from any one of Tables 3-5, 7 and 10. In some embodiments, the synthetic cytokine receptor can comprise any combination of one extracellular domain, one transmembrane domain, and one intracellular domain. Various combinations of extracellular, transmembrane and intracellular domains are provided in the exemplary synthetic cytokine receptors are set forth in Table 11.

[0344] In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from CD34 receptor. In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from DAP12 receptor. In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from a GpA receptor. In some embodiments, the extracellular domain derived from GpA comprises the sequence of amino acids in SEQ ID NO: 16. In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from a GpA receptor that is further truncated (i.e., tGpA in Table 11). In some embodiments, the truncated GpA extracellular domain comprises the sequence of amino acids in SEQ ID NO: 17. In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from a CD8 receptor. In some embodiments, the extracellular domain derived from CD8 comprises the sequence of amino acids in SEQ ID NO: 185. In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from a CD8 receptor that is further truncated (i.e., tCD8 in Table 11). In some embodiments, the truncated CD8 extracellular domain comprises the sequence of amino acids in SEQ ID NO: 19. In some embodiments, the synthetic cytokine receptor can comprise an extracellular domain derived from Muc24 receptor.

[0345] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from IL7R receptor. In some embodiments, the transmembrane domain derived from IL7R comprises a variant of wild-type IL7R (e.g., IL7R* and IL7R*2 in Table 11) with reference to SEQ ID NO: 71. In some embodiments, the variant of wild-type IL7R (SEQ ID NO: 71) comprises one or more amino acid insertions. In some embodiments, the variant of wild-type IL-7R comprises a trimer peptide. In some embodiments, the trimer comprises a cysteine. In some embodiments, the trimer comprises a proline. In some embodiments, the trimer comprises a threonine. In some embodiments, the trimer peptide comprises CPT. In some embodiments, the variant of IL7R comprises the sequence of amino acids set forth in SEQ ID NO: 6 (i.e., IL7R* in Table 11). In some embodiments, the variant of IL7R further comprises one or more amino acid substitutions and insertions at the C-terminus domain with reference to SEQ ID NO: 6 or SEQ ID NO: 71. In some embodiments, the one or more amino acid substitutions comprises a W to K substitution. In some embodiments, the one or more amino acid insertions comprises insertion of a K. In some embodiments, the one or more amino acid insertions comprises insertion of a R. In some30761-20002.40 embodiments, the one or more amino acid insertions comprises insertion of a I. In some embodiments, the one or more amino acid insertions comprises insertion of a K, R and I. In some embodiments, the variant of IL7R comprises the sequence of amino acids set forth in SEQ ID NO: 7 (i.e., IL7R*2 in Table 11).

[0346] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from Muc24 receptor.

[0347] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from TACI receptor.

[0348] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from CPT1 receptor.

[0349] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from DR5 receptor.

[0350] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from GpA receptor.

[0351] In some embodiments, the synthetic cytokine receptor can comprise a transmembrane domain derived from a GpA receptor that is modified (i.e., tGpA* in Table 11). In some embodiments, the modified GpA transmembrane domain comprises one or more amino acid deletions. In some embodiments, the modified GpA transmembrane domain comprises one or more amino acid deletions at the C-terminus. In some embodiments, the GpA transmembrane domain comprises the sequence of amino acids in SEQ ID NO: 22. In some embodiments, the modified GpA transmembrane domain (i.e., tGPA in Table 11) comprises the sequence of amino acids in SEQ ID NO: 43.

[0352] In some embodiments, the synthetic cytokine receptor can comprise an intracellular domain derived from wild-type IL9R receptor. In some embodiments, the synthetic cytokine receptor can comprise an intracellular domain derived from wild-type IL9R that is further modified. In some embodiments, the modification comprises a truncation or deletion of one or more amino acid residues. In some embodiments, the modification can comprise a insertion of one or more amino acid residues. As discussed in Section II.C.1.a., in some embodiments, the synthetic cytokine receptor can comprise a intracellular domain derived from wild-type IL9R (i.e., SEQ ID NO: 8 in Table 11). As discussed in Section II.C.1.b., in some embodiments, the synthetic cytokine receptor can comprise an intracellular domain derived from wild-type IL9R, which is further truncated (i.e., SEQ ID NOS: 51-56 in Table 11). As discussed in Section II.C.2., in some embodiments, the synthetic cytokine receptor can comprise a chimeric JAK / STAT fusion (i.e., SEQ ID NOS: 114, 116 and 181 in Table 11). Also provided are variants of any such SEQ ID NO (e.g., sequence that exhibits at least about 90% identity, at least about 91% identity, at least about 92% identity, at least about 93% identity, at least about 94% identity, at least about 95% identity, such as at least about 96% identity, 97% identity, 98% identity, or 99% identity to any one of SEQ ID NOS: 31-42, 47-50, and 58-64), in which the resulting synthetic30761-20002.40 cytokine receptor containing such a variant IL-9R intracellular domain is able to constitutively multimerize (e.g., dimerize) to result in constitutive activation of downstream signaling molecules.

[0353] In some embodiments, any of such sequence set forth by a respective SEQ ID NO also can contain an N-terminal signal sequence. In some embodiments, the signal sequence is a heterologous signal sequence that is not naturally contiguous in a wild-type sequence. In some embodiments, the signal sequence is a natural signal sequence contiguous to the extracellular domain sequence. In some embodiments, the signal sequence is a CD34 signal peptide MLVRRGARAGPRMPRGWTALCLLSLLPSGFM (SEQ ID NO:1). In some embodiments, the signal sequence is a DAP12 signal peptide MGGLEPCSRLLLLPLLLAVSGLRPVQA (SEQ ID NO:12).

[0354] In some embodiments, any of such sequence set forth by a respective SEQ ID NO may further include a tag or other sequence to facilitate detection of an expressed protein. In some embodiments, the sequence is a fluorescent moiety or is a peptide tag sequence. For instance a peptide tag may include a Flag tag, a Rho1D4-tag, a Myc tag, a His tag, CL7 tag, an HA tag or a V5 tag. In some embodiments, the sequence is a Flag Tag (DYKDDDDK; SEQ ID NO:3).30761-20002.4030761-20002.4030761-20002.40

[0355] In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 31. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 31. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 9. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 9. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 65. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 65. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 65. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 10. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 10. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 66. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 66. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 66. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 11. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 11. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 67. In30761-20002.40 some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 67. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 12. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 12. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 32. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 24. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 24. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 24. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 33. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 33. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 25. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 25.In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 25. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 34. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 34. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 34. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%,30761-20002.40 about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 26. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 26. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 26. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 35. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 27. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 27. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 36. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 28. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 28. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 28. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 38. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 38. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 38. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 29. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 29. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 29. In some30761-20002.40 embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 37. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 37. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 37. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 30. In some embodiments, the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 30. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 30. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 39. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 39. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 39. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 40. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 40. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 40. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 41. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 41. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 42. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 42. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 42. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 47. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in30761-20002.40 SEQ ID NO: 47. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 47. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 48. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 48. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 49. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 49. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 49. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 50. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 50. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 50. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 58. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 58. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 59. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 59. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 59. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 60. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 60. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 60. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about30761-20002.40 98%, or about 99% identical to SEQ ID NO: 61. In some embodiments, the synthetic cytokine receptor comprises the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the synthetic cytokine receptor consists of the amino acid sequence set forth in SEQ ID NO: 61. In some embodiments, the synthetic cytokine receptor comprises a sequence of amino acids that is at least about 70%, about 75%, about 80%, about 85%, about 90%, about 9...

Claims

30761-20002.40 WHAT IS CLAIMED:

1. A synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an intracellular domain capable of interleukin 9 receptor (IL-9R) signaling.

2. The synthetic cytokine receptor of claim 1, wherein the intracellular domain capable of IL-9R signaling comprises an IL-9R intracellular domain or a variant thereof.

3. The synthetic cytokine receptor of claim 1 or claim 2, wherein the intracellular domain capable of IL-9R signaling comprises a chimeric JAK / STAT fusion domain.

4. A synthetic cytokine receptor, comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or a variant thereof, wherein the synthetic cytokine receptor is a constitutively active cytokine receptor.

5. The synthetic cytokine receptor of any of claims 1 to 4, wherein the synthetic cytokine receptor is a multimer.

6. The synthetic cytokine receptor of any of claims 2 to 5 that is a multimer of identical polypeptide chains each comprising the extracellular domain, the transmembrane domain and the IL-9R intracellular domain or variant thereof.

7. The synthetic cytokine receptor of claim 5 or claim 6, wherein the multimer is a dimer.

8. The synthetic cytokine receptor of claim 7, wherein the dimer is a homodimer.

9. The synthetic cytokine receptor of any of claims 1 to 8, wherein each polypeptide chain is constitutively multimerized.

10. The synthetic cytokine receptor of any of claims 1 to 9, wherein the synthetic cytokine receptor comprises at least one self-assembly domain.30761-20002.40 11. The synthetic cytokine receptor of claim 10, wherein the at least one self- assembly domain is the extracellular domain and / or the transmembrane domain.

12. The synthetic cytokine receptor of any of claims 1 to 11, wherein the synthetic cytokine receptor is multimerized through the transmembrane domain and / or the extracellular domain.

13. The synthetic cytokine receptor of any of claims 1 to 12, wherein the synthetic cytokine receptor is multimerized through the transmembrane domain and the extracellular domain.

14. A synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or a variant thereof.

15. The synthetic cytokine receptor of any of claims 1 to 14, wherein the extracellular domain and / or the transmembrane domain are heterologous to the IL-9R.

16. The synthetic cytokine receptor of any of claims 1 to 15, wherein the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from the same protein.

17. The synthetic cytokine receptor of any of claims 1 to 15, wherein the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from different proteins.

18. The synthetic cytokine receptor of any of claims 1 to 17, wherein the transmembrane domain is 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 amino acids in length.

19. The synthetic cytokine receptor of any of claims 1 to 18, wherein the transmembrane domain comprises a transmembrane domain derived from Glycophorin A30761-20002.40 (GpA) Carnitine palmitoyltransferase 1 (CPT1), a tumor necrosis factor receptor (TNFR) or Muc24.

20. The synthetic cytokine receptor of any of claims 1 to 18, wherein the transmembrane domain comprises a transmembrane domain derived from Thrombopoietin receptor.

21. The synthetic cytokine receptor of any of claims 1 to 20, wherein the transmembrane domain promotes alpha-helix dimerization.

22. The synthetic cytokine receptor of any of claims 1 to 21, wherein the transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68).

23. The synthetic cytokine receptor of any of claims 1 to 21, wherein the transmembrane domain comprises the motif LIxxGVxxGVxxT (SEQ ID NO: 70).

24. The synthetic cytokine receptor of any of claims 1 to 23, wherein the transmembrane domain is a transmembrane domain derived from Glycophorin A (GpA) or a variant thereof that comprises one or more mutations (e.g, 1, 2, 3, 4, 5 or 6 mutations) compared to a wild-type GpA transmembrane domain, wherein the variant GpA is sufficient to promote alpha-helix dimerization.

25. The synthetic cytokine receptor of any of claims 1 to 24, wherein the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA).

26. The synthetic cytokine receptor of any of claims 1 to 25, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 22 or SEQ ID NO:

43.

27. The synthetic cytokine receptor of any of claims 1 to 26, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 43.30761-20002.40 28. The synthetic cytokine receptor of any of claims 1 to 22, wherein the transmembrane domain comprises GXXXG (SEQ ID NO: 68) and GXXXA (SEQ ID NO: 69) motifs.

29. The synthetic cytokine receptor of any of claims 1 to 22 and 28, wherein the transmembrane domain comprises a transmembrane domain derived from Carnitine palmitoyltransferase 1 (CPT1).

30. The synthetic cytokine receptor of any of claims 1 to 22, 28 and 29, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

45.

31. The synthetic cytokine receptor of any of claims 1 to 22 and 28 to 30, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

45.

32. The synthetic cytokine receptor of any of claims 1 to 21, wherein the synthetic cytokine receptor comprises the motif AXXXA (SEQ ID NO:77) or AXXXS (SEQ ID NO: 78).

33. The synthetic cytokine receptor of any of claims 1 to 22 or 32, wherein the synthetic cytokine receptor comprises the motif ĭPXĭ (SEQ ID NO:75) or ĭTXXAĭ (SEQ ID NO: 76).

34. The synthetic cytokine receptor of any of claims 1 to 22, 32 or 33, wherein the transmembrane domain is derived from a TNFR.

35. The synthetic cytokine receptor of claim 34, wherein the TNFR is TACI, DR5, p75NTR, Fas, TNFR1, TNFR2 or OX40.

36. The synthetic cytokine receptor of any of claims 1 to 22, and 32 to 35, wherein the transmembrane domain comprises a transmembrane domain derived from DR5.30761-20002.40 37. The synthetic cytokine receptor of any of claims 1 to 22, and 32 to 36, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

46.

38. The synthetic cytokine receptor of any of claims 1 to 22 and 32 to 37, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

46.

39. The synthetic cytokine receptor of any of claims 1 to 22, and 32 to 36, wherein the transmembrane domain comprises a transmembrane domain derived from TACI.

40. The synthetic cytokine receptor of any of claims 1 to 22, 32 to 36 and 39, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

44.

41. The synthetic cytokine receptor of any of claims 1 to 23, 32 to 36, 39 and 40, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

44.

42. The synthetic cytokine receptor of any of claims 1 to 19, wherein the transmembrane domain comprises 1 to 6 cysteine residues.

43. The synthetic cytokine receptor of any of claims 1 to 19 and 42, wherein the transmembrane domain promotes disulfide-linked dimerization.

44. The synthetic cytokine receptor of claim 43, wherein the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

45. The synthetic cytokine receptor of any of claims 1 to 19 and 42-44, wherein the transmembrane domain is a variant transmembrane domain that comprises one or more mutations compared to a wild-type transmembrane domain to promote homodimerization of the receptor polypeptide.

46. The synthetic cytokine receptor of claim 45, wherein the one or more mutations promote alpha-helix dimerization or disulfide-linked dimerization.30761-20002.40 47. The synthetic cytokine receptor of claim 45 or claim 46, wherein the one or more mutations introduces at least one cysteine into the transmembrane domain.

48. The synthetic cytokine receptor of any of claims 45 to 47, wherein the one or more mutations introduces a proline into the transmembrane domain.

49. The synthetic cytokine receptor of any of claims 45 to 47, wherein the one or more mutations introduces a threonine into the transmembrane domain.

50. The synthetic cytokine receptor of any of claims 45 to 49, wherein the one or more mutations introduces a trimer peptide of cysteine, proline, and another amino acid other than cysteine or proline into the transmembrane domain.

51. The synthetic cytokine receptor of any of claims 45-50, wherein the one or more mutations introduces a trimer peptide of cysteine, proline, threonine (CPT or TCP) into the transmembrane domain.

52. The synthetic cytokine receptor of any of claims 45-51, wherein the transmembrane domain is a variant IL-7R transmembrane domain and the one or more mutations is in the wild-type transmembrane sequence PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 71).

53. The synthetic cytokine receptor of any of claims 1 to 19 and 42 to 52, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 6, SEQ ID NO:7 or SEQ ID NO:

21.

54. The synthetic cytokine receptor of any of claims 1 to 19 and 42 to 53, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO:

21.

55. The synthetic cytokine receptor of any of claims 1 to 19, wherein the transmembrane domain comprises a transmembrane domain derived from Muc24.30761-20002.40 56. The synthetic cytokine receptor of any of claims 1 to 19 and 55, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

23.

57. The synthetic cytokine receptor of any of claims 1 to 19, 55 or 56, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

23.

58. The synthetic cytokine receptor of any of claims 1 to 57, wherein the extracellular domain is between about 150 to 260 amino acids in length.

59. The synthetic cytokine receptor of any of claims 1 to 58, wherein the extracellular domain is a dimerizing domain.

60. The synthetic cytokine receptor of claim 59, wherein the dimerizing domain comprises a hinge region.

61. The synthetic cytokine receptor of any of claims 1 to 60, wherein the extracellular domain promotes disulfide-linked dimerization.

62. The synthetic cytokine receptor of any of claims 1 to 61, wherein the extracellular domain comprises 1 to 6 cysteine residues.

63. The synthetic cytokine receptor of claim 61 or claim 62, wherein the disulfide- linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

64. The synthetic cytokine receptor of any of claims 1 to 63, wherein the extracellular domain is derived from the extracellular domain of CD34, DAP12, Glycophorin A, CD8, or Muc24.

65. The synthetic cytokine receptor of any of claims 1 to 63, wherein the extracellular domain comprises an extracellular domain derived from Thrombopoietin receptor.30761-20002.40 66. The synthetic cytokine receptor of any of claims 1 to 65, wherein the extracellular domain comprises an extracellular domain of CD8 or a truncated portion thereof comprising at least one cysteine residue.

67. The synthetic cytokine receptor of any of claims 1 to 66, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 18, SEQ ID NO: 185 or SEQ ID NO:

19.

68. The synthetic cytokine receptor of any of claims 1 to 67, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 18, SEQ ID NO: 185 or SEQ ID NO:

19.

69. The synthetic cytokine receptor of any of claims 1 to 65, wherein the extracellular domain comprises an extracellular domain of CD34 or a truncated portion thereof comprising at least one cysteine residue.

70. The synthetic cytokine receptor of any of claims 1 to 65 and 69, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

4.

71. The synthetic cytokine receptor of any of claims 1 to 65, 69 and 70, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO:

4.

72. The synthetic cytokine receptor of any of claims 1 to 65, wherein the extracellular domain is an extracellular domain of Muc24 or a truncated portion thereof comprising at least one cysteine residue.

73. The synthetic cytokine receptor of any of claims 1 to 65 and 72, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

20.

74. The synthetic cytokine receptor of any of claims 1 to 65, 72 and 73, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 20.30761-20002.40 75. The synthetic cytokine receptor of any of claims 1 to 65, wherein the extracellular domain is an extracellular domain of DAP12 or a truncated portion thereof comprising at least one cysteine residue.

76. The synthetic cytokine receptor of any of claims 1 to 65 and 75, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

5.

77. The synthetic cytokine receptor of any of claims 1 to 65, 75 and 76, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO:

5.

78. The synthetic cytokine receptor of any of claims 1 to 65, wherein the extracellular domain is an extracellular domain of Glycophorin A (GpA) or a truncated portion thereof comprising at least one cysteine residue.

79. The synthetic cytokine receptor of any of claims 1 to 65 and 78, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 16 or SEQ ID NO:

17.

80. The synthetic cytokine receptor of any of claims 1 to 65, 78 and 79, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 16 or SEQ ID NO:

17.

81. The synthetic cytokine receptor of any of claims 2 to 80, wherein the IL-9R intracellular domain or variant thereof is about 100 to 260 amino acids in length.

82. The synthetic cytokine receptor of any of claims 2 to 81, wherein the IL-9R intracellular domain or variant thereof comprises a BOX1 motif and / or a BOX2 motif.

83. The synthetic cytokine receptor of any of claims 2 to 82, wherein the IL-9R intracellular domain or variant thereof comprises a BOX2 motif.

84. The synthetic cytokine receptor of any of claims 2 and 4 to 80, wherein the IL- 9R intracellular domain or variant thereof is 230 amino acids in length.30761-20002.40 85. The synthetic cytokine receptor of any of claims 1 to 84, wherein the IL-9R intracellular domain or variant thereof is wild-type IL-9R intracellular domain or a variant thereof that comprises one or more mutations compared to the wild-type IL-9R intracellular domain set forth in SEQ ID NO:

8.

86. The synthetic cytokine receptor of claim 85, wherein the one or more mutations comprises one or more amino acid insertions, deletions, and / or substitutions.

87. The synthetic cytokine receptor of claim 85 or claim 86, wherein the one or more mutations promote signaling through STAT1, STAT3, and / or STAT5 pathways.

88. The synthetic cytokine receptor of any of claims 1 to 87, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

8.

89. The synthetic cytokine receptor of any of claims 1 to 88, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO:

8.

90. The synthetic cytokine receptor of any of claims 1 to 87, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO:

56.

91. The synthetic cytokine receptor of any of claims 1 to 87 and 90, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO:

56.

92. The synthetic cytokine receptor of any of claims 1 to 91, wherein the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50,30761-20002.40 SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO:

67.

93. The synthetic cytokine receptor of any of claims 1 to 92, wherein the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO:

67.

94. The synthetic cytokine receptor of any of claims 2 to 87, wherein the IL-9R intracellular domain or variant thereof comprises one or more amino acid deletions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).

95. The synthetic cytokine receptor of any of claims 2 to 87, wherein the IL-9R intracellular domain or variant thereof is a truncated IL-9R that lacks a contiguous sequence of amino acids at the C-terminus of wild-type IL-9R intracellular domain.

96. The synthetic cytokine receptor of claim 95, wherein the truncated IL-9R intracellular domain or variant thereof is truncated by between 62 and 99 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain.

97. The synthetic cytokine receptor of any of claims 2 to 87, wherein the IL-9R intracellular domain or variant thereof is a truncated IL-9R that lacks amino acids 132 to 230 of SEQ ID NO:8 or lacks amino acids 134 to 230 of SEQ ID NO:

8.

98. The synthetic cytokine receptor of any of claims 2 to 97, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO:

104.

99. The synthetic cytokine receptor of any of claims 2 to 98, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO: 104.30761-20002.40 100. The synthetic cytokine receptor of any of claims 2 to 99, wherein the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO:

63.

101. The synthetic cytokine receptor of any of claims 2 to 100, wherein the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO:

63.

102. The synthetic cytokine receptor of any of claims 2 to 87, wherein the IL-9R intracellular domain or variant thereof comprises one or more amino acid substitutions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).

103. The synthetic cytokine receptor of claim 102, wherein the IL-9R intracellular domain or variant thereof comprises a STAT binding motif or a variant thereof.

104. The synthetic cytokine receptor of claim 103, wherein the STAT binding motif comprises a STAT1, STAT3, and / or STAT5 binding motif.

105. The synthetic cytokine receptor of claim 103 or claim 104, wherein the STAT binding motif comprises YLPQ (SEQ ID NO: 171).

106. The synthetic cytokine receptor of any of claims 103 to 105, wherein the STAT binding motif comprises a variant STAT binding motif.

107. The synthetic cytokine receptor of any of claims 103 to 106, wherein the variant STAT binding motif comprises YRPQ (SEQ ID NO: 172).

108. The synthetic cytokine receptor of any of claims 103 to 106, wherein the variant STAT binding motif comprises YLPL (SEQ ID NO: 173).

109. The synthetic cytokine receptor of any of claims 103 to 106, wherein the variant STAT binding motif comprises YLKQ (SEQ ID NO: 174).30761-20002.40 110. The synthetic cytokine receptor of any of claims 2 to 109, wherein the variant IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO:

109.

111. The synthetic cytokine receptor of any of claims 2 to 110, wherein the variant IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO:

109.

112. The synthetic cytokine receptor of claim 3, wherein the chimeric JAK / STAT fusion domain comprises a JAK binding domain from a type I cytokine receptor and a STAT binding domain from an IL-9R intracellular domain.

113. The synthetic cytokine receptor of claim 112, wherein the IL-9R STAT binding domain comprises amino acid residues 73 to 230 of SEQ ID NO:

8.

114. The synthetic cytokine receptor of claim 112 or claim 113, wherein the STAT binding domain is 59 to 158 amino acids in length and comprises an IL-9R STAT binding motif.

115. The synthetic cytokine receptor of claim 114, wherein the IL-9R STAT binding motif comprises YLPQ (SEQ ID NO: 171).

116. The synthetic cytokine receptor of any of claims 112 to 115, wherein the IL- 9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the N-terminus of SEQ ID NO:

8.

117. The synthetic cytokine receptor of any of claims 112 to 116, wherein the IL- 9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the C-terminus of SEQ ID NO:

8.

118. The synthetic cytokine receptor of any of claims 112 to 117, wherein the IL- 9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 1 to 72 and / or 132 to 230 of SEQ ID NO: 8.30761-20002.40 119. The synthetic cytokine receptor of any of claims 112 to 118, wherein the IL- 9R STAT binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 122 or SEQ ID NO:

123.

120. The synthetic cytokine receptor of any of claims 112 to 119, wherein the IL- 9R STAT binding domain comprises an amino acid sequence of SEQ ID NO: 122 or SEQ ID NO:

123.

121. The synthetic cytokine receptor of any of claims 112 to 120, wherein the type I cytokine receptor is selected from the group consisting of interleukin 2 receptor (IL-2R), interleukin 4 receptor (IL-4R), interleukin 7 receptor (IL-7R), interleukin 13 receptor (IL- 13R), interleukin 15 receptor (IL-15R), and interleukin 2 receptor (IL-21R).

122. The synthetic cytokine receptor of any of claims 112 to 121, wherein the type I cytokine receptor is IL-7R.

123. The synthetic cytokine receptor of any of claims 112 to 122, wherein the IL- 7R JAK binding domain is 65 amino acids in length and comprises a box 1 motif.

124. The synthetic cytokine receptor of any of claims 112 to 123, wherein the IL- 7R JAK binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

121.

125. The synthetic cytokine receptor of claim 112 to 124, wherein the IL-7R JAK binding domain comprises an amino acid sequence of SEQ ID NO:

121.

126. The synthetic cytokine receptor of any of claims 112 to 125, wherein the chimeric JAK / STAT fusion domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 114, SEQ ID NO: 116 or SEQ ID NO:

181.

127. The synthetic cytokine receptor of any of claims 112 to 126, wherein the chimeric JAK / STAT fusion domain comprises an amino acid sequence of SEQ ID NO: 114, SEQ ID NO: 116, or SEQ ID NO: 181.30761-20002.40 128. The synthetic cytokine receptor of any of claims 1 to 127, wherein the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO:

117.

129. The synthetic cytokine receptor of any of claims 1 to 128, wherein the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO:

117.

130. The synthetic cytokine receptor of any of claims 1 to 3 and 14 to 129, wherein the synthetic cytokine receptor is a constitutively active cytokine receptor.

131. The synthetic cytokine receptor of any of claims 1 to 130, wherein the synthetic cytokine receptor elicits signaling through STAT1, STAT3, and / or STAT5 pathways.

132. The synthetic cytokine receptor of claim 131, wherein signaling through STAT1, STAT3, and / or STAT5 is increased compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R.

133. The synthetic cytokine receptor of claim 131 or claim 132, wherein signaling through STAT1, STAT3, and / or STAT5 is sustained for a longer period of time compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R.

134. The synthetic cytokine receptor of claim 133, wherein sustained STAT1, STAT3, and / or STAT5 signaling is determined by phosphorylation status of STAT1, STAT3, and / or STAT5.

135. A polynucleotide encoding the synthetic cytokine receptor of any of claims 1 to 134.

136. A vector, comprising the polynucleotide of claim 135, optionally wherein the vector is a viral vector.30761-20002.40 137. A method of engineering an isolated cell, comprising contacting the cell with the polynucleotide of claim 135 or the vector of claim 136.

138. An engineered cell expressing the synthetic cytokine receptor of any of claims 1 to 137.

139. An engineered cell expressing a synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an intracellular domain capable of interleukin 9 receptor (IL-9R) signaling.

140. The engineered cell of claim 139, wherein the intracellular domain capable of IL-9R signaling comprises an IL-9R intracellular domain or a variant thereof.

141. The engineered cell of claim 139 or claim 140, wherein the intracellular domain capable of IL-9R signaling comprises a chimeric JAK / STAT fusion domain.

142. An engineered cell expressing a synthetic cytokine receptor, wherein the synthetic cytokine receptor comprises an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or a variant thereof, wherein the synthetic cytokine receptor is a constitutively active cytokine receptor.

143. The engineered cell of any of claims 139 to 142, wherein the synthetic cytokine receptor is a multimer.

144. The engineered cell of any of claims 139 to 142, wherein the synthetic cytokine receptor is a multimer of identical polypeptide chains each comprising the extracellular domain, the transmembrane domain and the IL-9R intracellular domain or a variant thereof.

145. The engineered cell of claim 143 or claim 144 , wherein the multimer is a dimer.

146. The engineered cell of claim 145, wherein the dimer is a homodimer.30761-20002.40 147. The engineered cell of any of claims 138 to 146, wherein each polypeptide chain is constitutively multimerized 148. The engineered cell of any of claims 139 to 147, wherein the synthetic cytokine receptor comprises at least one self-assembly domain.

149. The engineered cell of claim 148, wherein the at least one self-assembly domain is the extracellular domain and / or the transmembrane domain.

150. The engineered cell of any of claims 139 to 149, wherein the synthetic cytokine receptor is multimerized through the transmembrane domain and / or the extracellular domain.

151. The engineered cell of any of claims 139 to 150, wherein the synthetic cytokine receptor is multimerized through the transmembrane domain and the extracellular domain.

152. An engineered cell expressing a synthetic cytokine receptor that is a homodimer of identical polypeptide chains each comprising an extracellular domain, a transmembrane domain, and an interleukin 9 receptor (IL-9R) intracellular domain or a variant thereof.

153. The engineered cell of any of claims 139 to 152, wherein the extracellular domain and / or the transmembrane domain are heterologous to the IL-9R.

154. The engineered cell of any of claims 139 to 153, wherein the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from the same protein.

155. The engineered cell of any of claims 139 to 153, wherein the transmembrane domain and extracellular domain are the transmembrane domain and extracellular domain from different proteins.30761-20002.40 156. The engineered cell of any of claims139 to 155, wherein the transmembrane domain is 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 amino acids in length.

157. The engineered cell of any of claims 139 to 156, wherein the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA) Carnitine palmitoyltransferase 1 (CPT1), a tumor necrosis factor receptor (TNFR) or Muc24.

158. The engineered cell of any of claims 139 to 156, wherein the transmembrane domain comprises a transmembrane domain derived from Thrombopoietin receptor.

159. The engineered cell of any of claims 139 to 158, wherein the transmembrane domain promotes alpha-helix dimerization.

160. The engineered cell of any of claims 139 to 159, wherein the transmembrane domain comprises the motif GXXXG (SEQ ID NO: 68).

161. The engineered cell of any of claims 139 to 159, wherein the transmembrane domain comprises the motif LixxGVxxGVxxT (SEQ ID NO: 70).

162. The engineered cell of any of claims 139 to 161, wherein the transmembrane domain is a transmembrane domain derived from Glycophorin A (GpA) or a variant thereof that comprises one or more mutations (e.g, 1, 2, 3, 4, 5 or 6 mutations) compared to a wild- type GpA transmembrane domain, wherein the variant GpA is sufficient to promote alpha- helix dimerization.

163. The engineered cell of any of claims 139 to 162, wherein the transmembrane domain comprises a transmembrane domain derived from Glycophorin A (GpA).

164. The engineered cell of any of claims 139 to 163, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 22 or SEQ ID NO:

43.

165. The engineered cell of any of claims 139 to 164, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22 or SEQ ID NO: 43.30761-20002.40 166. The engineered cell of any of claims 139 to 160, wherein the transmembrane domain comprises GXXXG (SEQ ID NO: 68) and GXXXA (SEQ ID NO: 69) motifs.

167. The engineered cell of any of claims 139 to 160 and 166, wherein the transmembrane domain comprises a transmembrane domain derived from Carnitine palmitoyltransferase 1 (CPT1).

168. The engineered cell of any of claims 139 to 160, 166 and 167, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

45.

169. The engineered cell of any of claims 139 to 160 and 166 to 168, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

45.

170. The engineered cell of any of claims 139 to 169, wherein the synthetic cytokine receptor comprises the motif AXXXA (SEQ ID NO:77) or AXXXS (SEQ ID NO: 78).

171. The engineered cell of any of claims 139 to 160 or 170, wherein the synthetic cytokine receptor comprises the motif ĭPXĭ (SEQ ID NO:75) or ĭTXXAĭ (SEQ ID NO: 76).

172. The engineered cell of any of claims 139 to 160, 170 or 171, wherein the transmembrane domain is derived from a TNFR.

173. The engineered cell of claim 172, wherein the TNFR is TACI, DR5, p75NTR, Fas, TNFR1, TNFR2 or OX40.

174. The engineered cell of any of claims 139 to 160, and 170 to 173, wherein the transmembrane domain comprises a transmembrane domain derived from DR5.30761-20002.40 175. The engineered cell of any of claims 139 to 160 and 170 to 174, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

46.

176. The engineered cell of any of claims 139 to 160 and 170 to 175, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

46.

177. The engineered cell of any of claims 139 to 160 and 170 to 174, wherein the transmembrane domain comprises a transmembrane domain derived from TACI.

178. The engineered cell of any of claims 139 to 160, 170 to 174 and 177, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

44.

179. The engineered cell of any of claims 39 to 161, 170 to 174, 177 and 178, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

44.

180. The engineered cell of any of claims 139 to 158, wherein the transmembrane domain comprises 1 to 6 cysteine residues.

181. The engineered cell of any of claims 139 to 158 and 180, wherein the transmembrane domain promotes disulfide-linked dimerization.

182. The engineered cell of claim 181, wherein the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

183. The engineered cell of any of claims 139 to 158 and 180 to 182, wherein the transmembrane domain is a variant transmembrane domain that comprises one or more mutations compared to a wild-type transmembrane domain to promote homodimerization of the receptor polypeptide.

184. The engineered cell of claim 183, wherein the one or more mutations promote alpha-helix dimerization or disulfide-linked dimerization.30761-20002.40 185. The engineered cell of claim 183 or claim 184, wherein the one or more mutations introduces at least one cysteine into the transmembrane domain.

186. The engineered cell of any of claims 183 to 185, wherein the one or more mutations introduces a proline into the transmembrane domain.

187. The engineered cell of any of claims 183 to 185, wherein the one or more mutations introduces a threonine into the transmembrane domain.

188. The engineered cell of any of claims 183 to 187, wherein the one or more mutations introduces a trimer peptide of cysteine, proline, and another amino acid other than cysteine or proline into the transmembrane domain.

189. The engineered cell of any of claims 183 to 188, wherein the one or more mutations introduces a trimer peptide of cysteine, proline, threonine (CPT or TCP) into the transmembrane domain.

190. The engineered cell of any of claims 183 to 188, wherein the transmembrane domain is a variant IL-7R transmembrane domain and the one or more mutations is in the wild-type transmembrane sequence PILLTISILSFFSVALLVILACVLW (SEQ ID NO: 71).

191. The engineered cell of any of claims 139 to 158 and 180 to 190, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 6, SEQ ID NO:7 or SEQ ID NO:

21.

192. The engineered cell of any of claims 139 to 158 and 180 to 191, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7 or SEQ ID NO:

21.

193. The engineered cell of any of claims 139 to 158, wherein the transmembrane domain comprises a transmembrane domain derived from Muc24.30761-20002.40 194. The engineered cell of any of claims 139 to 158 and 193, wherein the transmembrane domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

23.

195. The engineered cell of any of claims 139 to 158, 193 or 194, wherein the transmembrane domain comprises the amino acid sequence of SEQ ID NO:

23.

196. The engineered cell of any of claims 139 to 195, wherein the extracellular domain is between about 150 to 260 amino acids in length.

197. The engineered cell of any of claims 139 to 196, wherein the extracellular domain is a dimerizing domain.

198. The engineered cell of claim 197, wherein the dimerizing domain comprises a hinge region.

199. The engineered cell of any of claims 139 to 198, wherein the extracellular domain promotes disulfide-linked dimerization.

200. The engineered cell of any of claims 139 to 199, wherein the extracellular domain comprises 1 to 6 cysteine residues.

201. The engineered cell of claim 199 or claim 200, wherein the disulfide-linked dimerization forms 1 to 4 disulfide bridges between polypeptide chains of the synthetic cytokine receptor.

202. The engineered cell of any of claims 139 to 201, wherein the extracellular domain is derived from the extracellular domain of CD34, DAP12, Glycophorin A, CD8, or Muc24.

203. The engineered cell of any of claims 139 to 202, wherein the extracellular domain comprises an extracellular domain derived from Thrombopoietin receptor.30761-20002.40 204. The engineered cell of any of claims 139 to 203, wherein the extracellular domain comprises an extracellular domain of CD8 or a truncated portion thereof comprising at least one cysteine residue.

205. The engineered cell of any of claims 139 to 204, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 18 or SEQ ID NO:

19.

206. The engineered cell of any of claims 139 to 205, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO:

19.

207. The engineered cell of any of claims 139 to 203, wherein the extracellular domain comprises an extracellular domain of CD34 or a truncated portion thereof comprising at least one cysteine residue.

208. The engineered cell of any of claims 139 to 203 and 207, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

4.

209. The engineered cell of any of claims 139 to 203, 207 and 208, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO:

4.

210. The engineered cell of any of claims 139 to 203, wherein the extracellular domain is an extracellular domain of Muc24 or a truncated portion thereof comprising at least one cysteine residue.

211. The engineered cell of any of claims 139 to 203 and 210, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

20.

212. The engineered cell of any of claims 139 to 203, 210 and 211, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 20.30761-20002.40 213. The synthetic cytokine receptor of any of claims 139 to 203, wherein the extracellular domain is an extracellular domain of DAP12 or a truncated portion thereof comprising at least one cysteine residue.

214. The engineered cell of any of claims 139 to 203 and 213, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

5.

215. The engineered cell of any of claims 139 to 203, 213 and 214, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO:

5.

216. The synthetic cytokine receptor of any of claims 139 to 203, wherein the extracellular domain is an extracellular domain of Glycophorin A (GpA) or a truncated portion thereof comprising at least one cysteine residue.

217. The engineered cell of any of claims 139 to 203 and 216, wherein the extracellular domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 16 or SEQ ID NO:

17.

218. The engineered cell of any of claims 139 to 203, 216 and 217, wherein the extracellular domain comprises the amino acid sequence of SEQ ID NO: 16 or SEQ ID NO:

17.

219. The engineered cell of any of claims 139 to 218, wherein the IL-9R intracellular domain or variant thereof is about 100 to 260 amino acids in length.

220. The engineered cell of any of claims 139 to 219, wherein the IL-9R intracellular domain or variant thereof comprises a BOX1 motif and / or a BOX2 motif.

221. The engineered cell of any of claims 139 to 220, wherein the IL-9R intracellular domain or variant thereof comprises a BOX2 motif.

222. The engineered cell of any of claims 2 and 4 to 80, wherein the IL-9R intracellular domain or variant thereof is 230 amino acids in length.30761-20002.40 223. The engineered cell of any of claims 139 to 222, wherein the IL-9R intracellular domain or variant thereof is wild-type IL-9R intracellular domain or a variant thereof that comprises one or more mutations compared to the wild-type IL-9R intracellular domain set forth in SEQ ID NO:

8.

224. The engineered cell of any of claims 139 to 223, wherein the one or more mutations comprises one or more amino acid insertions, deletions, and / or substitutions.

225. The engineered cell of claim 223 or claim 224, wherein the one or more mutations promote signaling through STAT1, STAT3, and / or STAT5 pathways.

226. The engineered cell of any of claims 139 to 225, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

8.

227. The engineered cell of any of claims 139 to 226, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO:

8.

228. The engineered cell of any of claims 139 to 225, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO:

56.

229. The engineered cell of any of claims 139 to 225 and 228, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, or SEQ ID NO:

56.

230. The engineered cell of any of claims 139 to 229, wherein the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50,30761-20002.40 SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO:

67.

231. The engineered cell of any of claims 139 to 230, wherein the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 66 or SEQ ID NO:

67.

232. The engineered cell of any of claims 140 to 231, wherein the IL-9R intracellular domain or variant thereof comprises one or more amino acid deletions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).

233. The engineered cell of any of claims 140 to 232, wherein the IL-9R intracellular domain or variant thereof is a truncated IL-9R that lacks a contiguous sequence of amino acids at the C-terminus of wild-type IL-9R intracellular domain.

234. The engineered cell of claim 233, wherein the truncated IL-9R intracellular domain or variant thereof is truncated by between 62 and 99 contiguous amino acids from the C-terminus of wild-type IL-9R intracellular domain.

235. The engineered cell of any of claims 140 to 232, wherein the IL-9R intracellular domain or variant thereof is a truncated IL-9R that lacks amino acids 132 to 230 of SEQ ID NO:8 or lacks amino acids 134 to 230 of SEQ ID NO:

8.

236. The engineered cell of any of claims 140 to 235, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO:

104.

237. The engineered cell of any of claims 140 to 236, wherein the IL-9R intracellular domain or variant thereof comprises an amino acid sequence of SEQ ID NO: 54, SEQ ID NO: 103, or SEQ ID NO: 104.30761-20002.40 238. The engineered cell of any of claims 140 to 237, wherein the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO:

63.

239. The engineered cell of any of claims 140 to 238, wherein the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO:

63.

240. The engineered cell of any of claims 140 to 225, wherein the IL-9R intracellular domain or variant thereof comprises one or more amino acid substitutions with reference to wild-type IL-9R intracellular domain (SEQ ID NO: 8).

241. The engineered cell of claim 240, wherein the IL-9R intracellular domain or variant thereof comprises a STAT binding motif or a variant thereof.

242. The engineered cell of claim 241, wherein the STAT binding motif comprises a STAT1, STAT3, and / or STAT5 binding motif.

243. The engineered cell of claim 241 or claim 242, wherein the STAT binding motif comprises YLPQ (SEQ ID NO: 171).

244. The engineered cell of any of claims 241 to 243, wherein the STAT binding motif comprises a variant STAT binding motif.

245. The engineered cell of any of claims 241 to 244, wherein the variant STAT binding motif comprises YRPQ (SEQ ID NO: 172).

246. The engineered cell of any of claims 241 to 244, wherein the variant STAT binding motif comprises YLPL (SEQ ID NO: 173).

247. The engineered cell of any of claims 241 to 244, wherein the variant STAT binding motif comprises YLKQ (SEQ ID NO: 174).30761-20002.40 248. The engineered cell of any of claims 140 to 247, wherein the variant IL-9R intracellular domain or variant thereof comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO:

109.

249. The engineered cell of any of claims 140 to 248, wherein the variant IL-9R intracellular domain comprises an amino acid sequence of SEQ ID NO: 107 or SEQ ID NO: 108, or SEQ ID NO:

109.

250. The engineered cell of claim 141, wherein the chimeric JAK / STAT fusion domain comprises a JAK binding domain from a type I cytokine receptor and a STAT binding domain from an IL-9R intracellular domain.

251. The engineered cell of claim 250, wherein the IL-9R STAT binding domain comprises amino acid residues 73 to 230 of SEQ ID NO:

8.

252. The engineered cell of claim 250 or claim 251, wherein the STAT binding domain is 59 to 158 amino acids in length and comprises an IL-9R STAT binding motif.

253. The engineered cell of claim 252, wherein the IL-9R STAT binding motif comprises YLPQ (SEQ ID NO: 171).

254. The engineered cell of any of claims 250 to 253, wherein the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the N-terminus of SEQ ID NO:

8.

255. The engineered cell of any of claims 250 to 254, wherein the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks a contiguous sequence of amino acids at the C-terminus of SEQ ID NO:

8.

256. The engineered cell of any of claims 250 to 255, wherein the IL-9R STAT binding domain is a truncated IL-9R STAT binding domain that lacks amino acids at positions 1 to 72 and / or 132 to 230 of SEQ ID NO: 8.30761-20002.40 257. The engineered cell of any of claims 250 to 256, wherein the IL-9R STAT binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 122 or SEQ ID NO:

123.

258. The engineered cell of any of claims 250 to 257, wherein the IL-9R STAT binding domain comprises an amino acid sequence of SEQ ID NO: 122 or SEQ ID NO:

123.

259. The engineered cell of any of claims 250 to 258, wherein the type I cytokine receptor is selected from the group consisting of interleukin 2 receptor (IL-2R), interleukin 4 receptor (IL-4R), interleukin 7 receptor (IL-7R), interleukin 13 receptor (IL-13R), interleukin 15 receptor (IL-15R), and interleukin 2 receptor (IL-21R).

260. The engineered cell of any of claims 250 to 259, wherein the type I cytokine receptor is IL-7R.

261. The engineered cell of any of claims 250 to 260, wherein the IL-7R JAK binding domain is 65 amino acids in length and comprises a box 1 motif.

262. The engineered cell of any of claims 250 to 261, wherein the IL-7R JAK binding domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO:

121.

263. The engineered cell of claim 250 to 262, wherein the IL-7R JAK binding domain comprises an amino acid sequence of SEQ ID NO:

121.

264. The engineered cell of any of claims 250 to 263, wherein the chimeric JAK / STAT fusion domain comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 114, SEQ ID NO: 116 or SEQ ID NO:

181. 265 The engineered cell of any of claims 250 to 264, wherein the chimeric JAK / STAT fusion domain comprises an amino acid sequence of SEQ ID NO: 114, SEQ ID NO: 116 or SEQ ID NO: 181.30761-20002.40 266. The engineered cell of any of claims 139 to 265, wherein the synthetic cytokine receptor comprises an amino acid sequence that is at least about 85% identical to SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO:

117.

267. The engineered cell of any of claims 139 to 266, wherein the synthetic cytokine receptor comprises an amino acid sequence of SEQ ID NO: 113, SEQ ID NO: 115, or SEQ ID NO:

117.

268. The engineered cell of any of claims 139 to 141 and 152 to 267, wherein the synthetic cytokine receptor is a constitutively active cytokine receptor.

269. The engineered cell of any of claims 139 to 268, wherein the synthetic cytokine receptor elicits signaling through STAT1, STAT3, and / or STAT5 pathways.

270. The engineered cell of claim 269, wherein signaling through STAT1, STAT3, and / or STAT5 is increased compared to STAT1, STAT3, and / or STAT5 signaling via wild- type IL-9R.

271. The engineered cell of claim 269 or claim 270, wherein signaling through STAT1, STAT3, and / or STAT5 is sustained for a longer period of time compared to STAT1, STAT3, and / or STAT5 signaling via wild-type IL-9R.

272. The engineered cell of claim 271, wherein sustained STAT1, STAT3, and / or STAT5 signaling is determined by phosphorylation status of STAT1, STAT3, and / or STAT5.

273. The engineered cell of any of claims 139 to 272, wherein the engineered cell further expresses at least one different type of engineered receptor.

274. The engineered cell of claim 273, wherein the at least one different type of engineered receptor is a chimeric antigen receptor.

275. The engineered cell of claim 274, wherein the extracellular domain of the chimeric antigen receptor binds to an antigen expressed on a cancer cell.30761-20002.40 276. The engineered cell of claim 275, wherein the extracellular domain of the chimeric antigen receptor binds to an idiotype of an antibody.

277. The engineered cell of claim 276, wherein the antibody is against an antigen expressed on a cancer cell. 278 The engineered cell of claim 277, wherein the cancer cell is a blood cancer cell or a solid tumor cancer cell.

279. The engineered cell of any of claims 139 to 278, wherein the cell is an immune cell.

280. The engineered cell of any of claims 139 to 279, wherein the cell is a lymphocyte.

281. The engineered cell of any of claims 139 to 280, wherein the engineered cell is an immune effector cell.

282. The engineered cell of any of claims 139 to 281, wherein the cell is a T cell or a Natural Killer (NK) cell.

283. The engineered cell of claim 139 to 282, wherein the cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell.

284. The engineered cell of claim 283, wherein the immune effector cell is a cytotoxic T cell.

285. The engineered cell of claim 283, wherein the immune effector cell is a natural killer cell.

286. The engineered cell of any of claims 139 to 285, wherein the cell is a primary cell.30761-20002.40 287. The engineered cell of any of claims 139 to 286, wherein the cell is a human cell.

288. A population of cells, comprising at least one engineered cell of any of claims 139 to 287.

289. The population of cells of claim 288, wherein the at least one engineered cell comprises engineered CD4+ T cells and engineered CD8+ T cells.

290. A pharmaceutical composition comprising the engineered cell of any of claims 90 to 191 or the population of cells of claim 288 or claim 289.

291. The pharmaceutical composition of claim 290, wherein the pharmaceutical composition further comprises a pharmaceutical acceptable carrier.

292. The pharmaceutical composition of claim 290 or claim 291, wherein the pharmaceutical composition further comprises a cryoprotectant 293. The pharmaceutical composition of any of claims 290 to 292, for use in treating a cancer in a subject.

294. A method of treating a disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any of claims 290 to 293.

295. The method of claims 294, wherein the disease or condition is a cancer.

296. The method of claim 294 or claim 295, wherein the engineered cell of the pharmaceutical composition expresses an engineered antigen receptor that binds to an antigen expressed on a cell of the cancer.

297. The method of claim 296, wherein the engineered antigen receptor is a chimeric antigen receptor.30761-20002.40 298. The method of claim 296, wherein the engineered antigen receptor is a T cell receptor.

299. A method of improving function of an immune cell, comprising introducing to the immune cell the polynucleotide of claim 135 or the vector of claim 136, wherein improving immune cell function comprises increased STAT1, STAT3, and / or STAT5 signaling compared to an immune cell expressing wild-type IL-9R.

300. A method of improving cytotoxicity of an immune cell, comprising introducing to the immune cell the polynucleotide of claim 135 or the vector of claim 136, wherein improving immune cell cytotoxicity comprises increased target cell killing compared to an immune cell expressing wild-type IL-9R.

301. A method of improving viability of an immune cell, comprising introducing to the immune cell the polynucleotide of claim 135 or the vector of claim 136, wherein improving viability of the immune cell comprises decreased immune cell death compared to an immune cell expressing wild-type IL-9R.

302. A method of improving cytokine secretion by an immune cell, comprising introducing to the immune cell the polynucleotide of claim 135 or the vector of claim 136, wherein improving cytokine secretion comprises increased secretion of interferon compared to an immune cell expressing wild-type IL-9R.

303. The method of claim 302, wherein the interferon comprises IFNȖ.

304. The method of any of claims 299 to 303, wherein the immune cell further comprises an engineered antigen receptor.

305. The method of claim 304, wherein the one different type of engineered receptor is a chimeric antigen receptor (CAR).

306. The method of claim 305, wherein the extracellular domain of the CAR binds to an antigen expressed on a cancer cell.30761-20002.40 307. The method of claim 306, wherein the cancer cell is a blood cancer cell or a solid tumor cancer cell.

308. The method of any of claims 299 to 307, wherein the immune cell is a lymphocyte.

309. The method of any of claims 299 to 308, wherein the immune cell is an effector cell.

310. The method of any of claims 299 to 309, wherein the immune cell is a T cell or NK cell.

311. The method of any of claims 299 to 303, wherein the immune cell is a T cell.

312. The method of any of claims 299 to 310, wherein the immune cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell.

313. The method of any of claims 299 to 310, wherein the immune cell is a cytotoxic T cell.

314. The method of any of claims 299 to 311, wherein the immune cell is a NK cell.

315. The method of any of claims 299 to 313, wherein the immune cell is a primary cell.

316. A method of improving function of an immune cell, comprising introducing to the immune cell the polynucleotide of claim 135 or the vector of claim 136, thereby improving function of the immune cell.

317. The method of claim 316, wherein improving immune cell function comprises one or more of increased STAT signaling, increased cytotoxicity, increased proliferation, increased viability, increased cytokine secretion, and increased cytotoxic protein secretion compared to a reference cell.30761-20002.40 318. The method of claim 317, wherein the reference cell comprises a non- engineered immune cell or an engineered immune cell.

319. The method of claim 318, wherein the engineered immune cell expresses a engineered antigen receptor.

320. The method of claim 319, wherein the engineered antigen receptor is a wild- type IL-9R, a chimeric antigen receptor (CAR) or a T cell receptor (TCR).

321. The method of any of claims 317-320, wherein increased STAT signaling comprises increased STAT1, STAT3 and / or STAT5 signaling.

322. The method of any of claims 317-321, wherein increased cytotoxicity comprises increased killing of a target cell.

323. The method of any of claims 317-322, wherein increased cytokine secretion comprises increased secretion of one or more of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-10 (IL-10), and TNFĮ.

324. The method of any of claims 317-323, wherein increased cytotoxic protein secretion comprises increased secretion of one or more of granzyme A, granzyme B, granulysin and perforin.

325. The method of any of claims 317-324, wherein increased viability comprises decreased cell death.

326. The method of any of claims 316-325, wherein the immune cell is a lymphocyte.

327. The method of any of claims 316-326, wherein the immune cell is an effector cell.30761-20002.40 328. The method of any of claims 316-327, wherein the immune cell is a T cell or NK cell.

329. The method of any of claims 316-327, wherein the immune cell is a T cell and the T cell is a CD4+ T cell or a CD8+ T cell.

330. The method of any of claims 316-329, wherein the immune cell is a cytotoxic T cell.

331. The method of any of claims 316-328, wherein the immune cell is a NK cell.

332. The method of any of claims 316-331, wherein the immune cell is a primary cell.

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