Skip to main content

Advertisement

Log in

The common γ-chain cytokine receptor: tricks-and-treats for T cells

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Originally identified as the third subunit of the high-affinity IL-2 receptor complex, the common γ-chain (γc) also acts as a non-redundant receptor subunit for a series of other cytokines, collectively known as γc family cytokines. γc plays essential roles in T cell development and differentiation, so that understanding the molecular basis of its signaling and regulation is a critical issue in T cell immunology. Unlike most other cytokine receptors, γc is thought to be constitutively expressed and limited in its function to the assembly of high-affinity cytokine receptors. Surprisingly, recent studies reported a series of findings that unseat γc as a simple housekeeping gene, and unveiled γc as a new regulatory molecule in T cell activation and differentiation. Cytokine-independent binding of γc to other cytokine receptor subunits suggested a pre-association model of γc with proprietary cytokine receptors. Also, identification of a γc splice isoform revealed expression of soluble γc proteins (sγc). sγc directly interacted with surface IL-2Rβ to suppress IL-2 signaling and to promote pro-inflammatory Th17 cell differentiation. As a result, endogenously produced sγc exacerbated autoimmune inflammatory disease, while the removal of endogenous sγc significantly ameliorated disease outcome. These data provide new insights into the role of both membrane and soluble γc in cytokine signaling, and open new venues to interfere and modulate γc signaling during immune activation. These unexpected discoveries further underscore the perspective that γc biology remains largely uncharted territory that invites further exploration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rochman Y, Spolski R, Leonard WJ (2009) New insights into the regulation of T cells by γc family cytokines. Nat Rev Immunol 9:480–490

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Sugamura K, Asao H, Kondo M, Tanaka N, Ishii N, Ohbo K, Nakamura M, Takeshita T (1996) The interleukin-2 receptor γ chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol 14:179–205

    Article  PubMed  CAS  Google Scholar 

  3. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ (1993) Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157

    Article  PubMed  CAS  Google Scholar 

  4. Puck JM, Nussbaum RL, Conley ME (1987) Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation. J Clin Invest 79:1395–1400

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K (1995) Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor γ chain. Proc Natl Acad Sci USA 92:377–381

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I (1991) Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352:621–624

    Article  PubMed  CAS  Google Scholar 

  7. von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R (1995) Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J Exp Med 181:1519–1526

    Article  Google Scholar 

  8. Rodewald HR, Waskow C, Haller C (2001) Essential requirement for c-kit and common γ chain in thymocyte development cannot be overruled by enforced expression of Bcl-2. J Exp Med 193:1431–1437

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Sudo T, Nishikawa S, Ohno N, Akiyama N, Tamakoshi M, Yoshida H, Nishikawa S (1993) Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc Natl Acad Sci USA 90:9125–9129

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Bhatia SK, Tygrett LT, Grabstein KH, Waldschmidt TJ (1995) The effect of in vivo IL-7 deprivation on T cell maturation. J Exp Med 181:1399–1409

    Article  PubMed  CAS  Google Scholar 

  11. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151

    Article  PubMed  CAS  Google Scholar 

  12. Weinreich MA, Odumade OA, Jameson SC, Hogquist KA (2010) T cells expressing the transcription factor PLZF regulate the development of memory-like CD8+ T cells. Nat Immunol 11:709–716

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9:669–676

    Article  PubMed  CAS  Google Scholar 

  14. Oh S, Perera LP, Burke DS, Waldmann TA, Berzofsky JA (2004) IL-15/IL-15Rα-mediated avidity maturation of memory CD8+ T cells. Proc Natl Acad Sci USA 101:15154–15159

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C (2008) A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29:127–137

    Article  PubMed  CAS  Google Scholar 

  16. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29:138–149

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448:480–483

    Article  PubMed  CAS  Google Scholar 

  18. Hong C, Luckey MA, Ligons DL, Waickman AT, Park JY, Kim GY, Keller HR, Etzensperger R, Tai X, Lazarevic V, Feigenbaum L, Catalfamo M, Walsh ST, Park JH (2014) Activated T cells secrete an alternatively spliced form of common γ-chain that inhibits cytokine signaling and exacerbates inflammation. Immunity 40:910–923

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Walsh ST (2012) Structural insights into the common γ-chain family of cytokines and receptors from the interleukin-7 pathway. Immunol Rev 250:303–316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. McElroy CA, Holland PJ, Zhao P, Lim JM, Wells L, Eisenstein E, Walsh ST (2012) Structural reorganization of the interleukin-7 signaling complex. Proc Natl Acad Sci USA 109:2503–2508

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Pillet AH, Lavergne V, Pasquier V, Gesbert F, Theze J, Rose T (2010) IL-2 induces conformational changes in its preassembled receptor core, which then migrates in lipid raft and binds to the cytoskeleton meshwork. J Mol Biol 403:671–692

    Article  PubMed  CAS  Google Scholar 

  22. Linowes BA, Ligons DL, Nam AS, Hong C, Keller HR, Tai X, Luckey MA, Park JH (2013) Pim1 permits generation and survival of CD4+ T cells in the absence of γc cytokine receptor signaling. Eur J Immunol 43:2283–2294

    Article  PubMed  CAS  Google Scholar 

  23. de Saint Basile G, Arveiler B, Oberle I, Malcolm S, Levinsky RJ, Lau YL, Hofker M, Debre M, Fischer A, Griscelli C et al (1987) Close linkage of the locus for X chromosome-linked severe combined immunodeficiency to polymorphic DNA markers in Xq11–q13. Proc Natl Acad Sci USA 84:7576–7579

  24. Puck JM, Nussbaum RL, Smead DL, Conley ME (1989) X-linked severe combined immunodeficiency: localization within the region Xq13.1–q21.1 by linkage and deletion analysis. Am J Hum Genet 44:724–730

    PubMed  CAS  PubMed Central  Google Scholar 

  25. Puck JM, Deschenes SM, Porter JC, Dutra AS, Brown CJ, Willard HF, Henthorn PS (1993) The interleukin-2 receptor γ chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. Hum Mol Genet 2:1099–1104

    Article  PubMed  CAS  Google Scholar 

  26. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET et al (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor γ chain. Immunity 2:223–238

    Article  PubMed  CAS  Google Scholar 

  27. Gougeon ML, Drean G, Le Deist F, Dousseau M, Fevrier M, Diu A, Theze J, Griscelli C, Fischer A (1990) Human severe combined immunodeficiency disease: phenotypic and functional characteristics of peripheral B lymphocytes. J Immunol 145:2873–2879

    PubMed  CAS  Google Scholar 

  28. Matthews DJ, Clark PA, Herbert J, Morgan G, Armitage RJ, Kinnon C, Minty A, Grabstein KH, Caput D, Ferrara P et al (1995) Function of the interleukin-2 (IL-2) receptor γ-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15. Blood 85:38–42

    PubMed  CAS  Google Scholar 

  29. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 191:771–780

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Penit C, Lucas B, Vasseur F (1995) Cell expansion and growth arrest phases during the transition from precursor (CD48) to immature (CD4+8+) thymocytes in normal and genetically modified mice. J Immunol 154:5103–5113

    PubMed  CAS  Google Scholar 

  31. Nakajima H, Leonard WJ (1999) Role of Bcl-2 in αβ T cell development in mice deficient in the common cytokine receptor γ-chain: the requirement for Bcl-2 differs depending on the TCR/MHC affinity. J Immunol 162:782–790

    PubMed  CAS  Google Scholar 

  32. Kondo M, Akashi K, Domen J, Sugamura K, Weissman IL (1997) Bcl-2 rescues T lymphopoiesis, but not B or NK cell development, in common γ chain-deficient mice. Immunity 7:155–162

    Article  PubMed  CAS  Google Scholar 

  33. Nakajima H, Noguchi M, Leonard WJ (2000) Role of the common cytokine receptor γ chain (γc) in thymocyte selection. Immunol Today 21:88–94

    Article  PubMed  CAS  Google Scholar 

  34. DiSanto JP, Guy-Grand D, Fisher A, Tarakhovsky A (1996) Critical role for the common cytokine receptor γ chain in intrathymic and peripheral T cell selection. J Exp Med 183:1111–1118

    Article  PubMed  CAS  Google Scholar 

  35. McCaughtry TM, Etzensperger R, Alag A, Tai X, Kurtulus S, Park JH, Grinberg A, Love P, Feigenbaum L, Erman B, Singer A (2012) Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med 209:2263–2276

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Park JH, Adoro S, Lucas PJ, Sarafova SD, Alag AS, Doan LL, Erman B, Liu X, Ellmeier W, Bosselut R, Feigenbaum L, Singer A (2007) ‘Coreceptor tuning’: cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol 8:1049–1059

    Article  PubMed  CAS  Google Scholar 

  37. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL (1997) Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 89:1033–1041

    Article  PubMed  CAS  Google Scholar 

  38. von Freeden-Jeffry U, Solvason N, Howard M, Murray R (1997) The earliest T lineage-committed cells depend on IL-7 for Bcl-2 expression and normal cell cycle progression. Immunity 7:147–154

    Article  Google Scholar 

  39. Singer A, Adoro S, Park JH (2008) Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol 8:788–801

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Brugnera E, Bhandoola A, Cibotti R, Yu Q, Guinter TI, Yamashita Y, Sharrow SO, Singer A (2000) Coreceptor reversal in the thymus: signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Immunity 13:59–71

    Article  PubMed  CAS  Google Scholar 

  41. Yu Q, Park JH, Doan LL, Erman B, Feigenbaum L, Singer A (2006) Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection. J Exp Med 203:165–175

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Park JH, Adoro S, Guinter T, Erman B, Alag AS, Catalfamo M, Kimura MY, Cui Y, Lucas PJ, Gress RE, Kubo M, Hennighausen L, Feigenbaum L, Singer A (2010) Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells. Nat Immunol 11:257–264

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Puel A, Ziegler SF, Buckley RH, Leonard WJ (1998) Defective IL7R expression in TB+NK+ severe combined immunodeficiency. Nat Genet 20:394–397

    Article  PubMed  CAS  Google Scholar 

  44. Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K (1993) Sharing of the interleukin-2 (IL-2) receptor γ chain between receptors for IL-2 and IL-4. Science 262:1874–1877

    Article  PubMed  CAS  Google Scholar 

  45. Russell SM, Keegan AD, Harada N, Nakamura Y, Noguchi M, Leland P, Friedmann MC, Miyajima A, Puri RK, Paul WE et al (1993) Interleukin-2 receptor γ chain: a functional component of the interleukin-4 receptor. Science 262:1880–1883

    Article  PubMed  CAS  Google Scholar 

  46. Kimura Y, Takeshita T, Kondo M, Ishii N, Nakamura M, Van Snick J, Sugamura K (1995) Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex. Int Immunol 7:115–120

    Article  PubMed  CAS  Google Scholar 

  47. Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O et al (1994) Interaction of IL-2Rβ and γc chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266:1042–1045

    Article  PubMed  CAS  Google Scholar 

  48. Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D (1994) Utilization of the β and γ chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 13(12):2822–2830

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Asao H, Takeshita T, Ishii N, Kumaki S, Nakamura M, Sugamura K (1993) Reconstitution of functional interleukin 2 receptor complexes on fibroblastoid cells: involvement of the cytoplasmic domain of the γ chain in two distinct signaling pathways. Proc Natl Acad Sci USA 90:4127–4131

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ (1993) Interleukin-2 receptor γ chain: a functional component of the interleukin-7 receptor. Science 262:1877–1880

    Article  PubMed  CAS  Google Scholar 

  51. Herrmann T, Diamantstein T (1988) The high affinity interleukin 2 receptor: evidence for three distinct polypeptide chains comprising the high affinity interleukin 2 receptor. Mol Immunol 25:1201–1207

    Article  PubMed  CAS  Google Scholar 

  52. Arima N, Kamio M, Imada K, Hori T, Hattori T, Tsudo M, Okuma M, Uchiyama T (1992) Pseudo-high affinity interleukin 2 (IL-2) receptor lacks the third component that is essential for functional IL-2 binding and signaling. J Exp Med 176:1265–1272

    Article  PubMed  CAS  Google Scholar 

  53. Nakarai T, Robertson MJ, Streuli M, Wu Z, Ciardelli TL, Smith KA, Ritz J (1994) Interleukin 2 receptor γ chain expression on resting and activated lymphoid cells. J Exp Med 180:241–251

    Article  PubMed  CAS  Google Scholar 

  54. Boussiotis VA, Barber DL, Nakarai T, Freeman GJ, Gribben JG, Bernstein GM, D’Andrea AD, Ritz J, Nadler LM (1994) Prevention of T cell anergy by signaling through the γc chain of the IL-2 receptor. Science 266:1039–1042

    Article  PubMed  CAS  Google Scholar 

  55. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN et al (1994) Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 266:1045–1047

    Article  PubMed  CAS  Google Scholar 

  56. Kawamura M, McVicar DW, Johnston JA, Blake TB, Chen YQ, Lal BK, Lloyd AR, Kelvin DJ, Staples JE, Ortaldo JR et al (1994) Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci USA 91:6374–6378

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  57. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O’Shea JJ (1994) Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 370:151–153

    Article  PubMed  CAS  Google Scholar 

  58. Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C, Liu ET, Ihle JN (1994) Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 370:153–157

    Article  PubMed  CAS  Google Scholar 

  59. Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM Jr, Schreiber RD (1998) Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93:373–383

    Article  PubMed  CAS  Google Scholar 

  60. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin EF, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN (1998) Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93:385–395

    Article  PubMed  CAS  Google Scholar 

  61. Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K (1998) Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93:397–409

    Article  PubMed  CAS  Google Scholar 

  62. Shimoda K, Kato K, Aoki K, Matsuda T, Miyamoto A, Shibamori M, Yamashita M, Numata A, Takase K, Kobayashi S, Shibata S, Asano Y, Gondo H, Sekiguchi K, Nakayama K, Nakayama T, Okamura T, Okamura S, Niho Y, Nakayama K (2000) Tyk2 plays a restricted role in IFN α signaling, although it is required for IL-12-mediated T cell function. Immunity 13:561–571

    Article  PubMed  CAS  Google Scholar 

  63. Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, McCoy B, Bogdan C, Decker T, Brem G, Pfeffer K, Muller M (2000) Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity 13:549–560

    Article  PubMed  CAS  Google Scholar 

  64. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O’Shea JJ et al (1995) Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377:65–68

    Article  PubMed  CAS  Google Scholar 

  65. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, O’Shea JJ, Leonard WJ (1995) Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:797–800

    Article  PubMed  CAS  Google Scholar 

  66. Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270:794–797

    Article  PubMed  CAS  Google Scholar 

  67. Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP, Doherty PC, Grosveld GC, Ihle JN (1995) Defective lymphoid development in mice lacking Jak3. Science 270:800–802

    Article  PubMed  CAS  Google Scholar 

  68. Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N, Miyake K, Nakauchi H, Shirasawa T, Saito T (1995) Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3:771–782

    Article  PubMed  CAS  Google Scholar 

  69. Huang LJ, Constantinescu SN, Lodish HF (2001) The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell 8:1327–1338

    Article  PubMed  CAS  Google Scholar 

  70. Ragimbeau J, Dondi E, Alcover A, Eid P, Uze G, Pellegrini S (2003) The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. EMBO J 22:537–547

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Radtke S, Hermanns HM, Haan C, Schmitz-Van De Leur H, Gascan H, Heinrich PC, Behrmann I (2002) Novel role of Janus kinase 1 in the regulation of oncostatin M receptor surface expression. J Biol Chem 277:11297–11305

    Article  PubMed  CAS  Google Scholar 

  72. Suzuki K, Nakajima H, Saito Y, Saito T, Leonard WJ, Iwamoto I (2000) Janus kinase 3 (Jak3) is essential for common cytokine receptor γ chain (γc)-dependent signaling: comparative analysis of γc, Jak3, and γc and Jak3 double-deficient mice. Int Immunol 12:123–132

    Article  PubMed  CAS  Google Scholar 

  73. Hofmann SR, Lam AQ, Frank S, Zhou YJ, Ramos HL, Kanno Y, Agnello D, Youle RJ, O’Shea JJ (2004) Jak3-independent trafficking of the common γ chain receptor subunit: chaperone function of Jaks revisited. Mol Cell Biol 24:5039–5049

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. Sohn SJ, Forbush KA, Nguyen N, Witthuhn B, Nosaka T, Ihle JN, Perlmutter RM (1998) Requirement for Jak3 in mature T cells: its role in regulation of T cell homeostasis. J Immunol 160:2130–2138

    PubMed  CAS  Google Scholar 

  75. Kondo M, Ohashi Y, Tada K, Nakamura M, Sugamura K (1994) Expression of the mouse interleukin-2 receptor γ chain in various cell populations of the thymus and spleen. Eur J Immunol 24:2026–2030

    Article  PubMed  CAS  Google Scholar 

  76. Bani L, David D, Moreau JL, Cayota A, Nakarai T, Ritz J, Theze J (1997) Expression of the IL-2 receptor γ subunit in resting human CD4 T lymphocytes: mRNA is constitutively transcribed and the protein stored as an intracellular component. Int Immunol 9:573–580

    Article  PubMed  CAS  Google Scholar 

  77. Gesbert F, Malarde V, Dautry-Varsat A (2005) Ubiquitination of the common cytokine receptor γc and regulation of expression by an ubiquitination/deubiquitination machinery. Biochem Biophys Res Commun 334:474–480

    Article  PubMed  CAS  Google Scholar 

  78. Markiewicz S, Bosselut R, Le Deist F, de Villartay JP, Hivroz C, Ghysdael J, Fischer A, de Saint Basile G (1996) Tissue-specific activity of the γc chain gene promoter depends upon an Ets binding site and is regulated by GA-binding protein. J Biol Chem 271:14849–14855

    Article  PubMed  CAS  Google Scholar 

  79. Yu S, Zhao DM, Jothi R, Xue HH (2010) Critical requirement of GABPα for normal T cell development. J Biol Chem 285:10179–10188

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Kalia V, Sarkar S, Subramaniam S, Haining WN, Smith KA, Ahmed R (2010) Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32:91–103

    Article  PubMed  CAS  Google Scholar 

  81. Amorosi S, Russo I, Amodio G, Garbi C, Vitiello L, Palamaro L, Adriani M, Vigliano I, Pignata C (2009) The cellular amount of the common γ-chain influences spontaneous or induced cell proliferation. J Immunol 182(5):3304–3309

    Article  PubMed  CAS  Google Scholar 

  82. Orr SJ, Roessler S, Quigley L, Chan T, Ford JW, O’Connor GM, McVicar DW (2010) Implications for gene therapy-limiting expression of IL-2R γc delineate differences in signaling thresholds required for lymphocyte development and maintenance. J Immunol 185:1393–1403

    Article  PubMed  CAS  Google Scholar 

  83. Smyth CM, Ginn SL, Deakin CT, Logan GJ, Alexander IE (2007) Limiting γc expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors. Blood 110:91–98

    Article  PubMed  CAS  Google Scholar 

  84. Ginn SL, Smyth C, Wong M, Bennetts B, Rowe PB, Alexander IE (2004) A novel splice-site mutation in the common γ chain (γc) gene IL2RG results in X-linked severe combined immunodeficiency with an atypical NK+ phenotype. Hum Mutat 23:522–523

    Article  PubMed  CAS  Google Scholar 

  85. Zhou YJ, Chen M, Cusack NA, Kimmel LH, Magnuson KS, Boyd JG, Lin W, Roberts JL, Lengi A, Buckley RH, Geahlen RL, Candotti F, Gadina M, Changelian PS, O’Shea JJ (2001) Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Mol Cell 8:959–969

    Article  PubMed  CAS  Google Scholar 

  86. Wang X, Lupardus P, Laporte SL, Garcia KC (2009) Structural biology of shared cytokine receptors. Annu Rev Immunol 27:29–60

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Izuhara K, Miyajima A, Harada N (1993) The chimeric receptor between interleukin-2 receptor β chain and interleukin-4 receptor transduces interleukin-2 signal. Biochem Biophys Res Commun 190:992–1000

    Article  PubMed  CAS  Google Scholar 

  88. Katz G, Pobezinsky LA, Jeurling S, Shinzawa M, Van Laethem F, Singer A (2014) T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1. Sci Signal 7:ra83

  89. Lee IH, Li WP, Hisert KB, Ivashkiv LB (1999) Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion. J Exp Med 190:1263–1274

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  90. Zhu J, Huang H, Guo L, Stonehouse T, Watson CJ, Hu-Li J, Paul WE (2000) Transient inhibition of interleukin 4 signaling by T cell receptor ligation. J Exp Med 192:1125–1134

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  91. Kimura MY, Pobezinsky LA, Guinter TI, Thomas J, Adams A, Park JH, Tai X, Singer A (2013) IL-7 signaling must be intermittent, not continuous, during CD8+ T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14:143–151

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  92. Noguchi M, Sarin A, Aman MJ, Nakajima H, Shores EW, Henkart PA, Leonard WJ (1997) Functional cleavage of the common cytokine receptor γ chain (γc) by calpain. Proc Natl Acad Sci USA 94:11534–11539

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. Haan C, Rolvering C, Raulf F, Kapp M, Druckes P, Thoma G, Behrmann I, Zerwes HG (2011) Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors. Chem Biol 18:314–323

    Article  PubMed  CAS  Google Scholar 

  94. Gaffen SL (2001) Signaling domains of the interleukin 2 receptor. Cytokine 14:63–77

    Article  PubMed  CAS  Google Scholar 

  95. Nelson BH, McIntosh BC, Rosencrans LL, Greenberg PD (1997) Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor γc chain for Janus kinase activation leading to T cell proliferation. Proc Natl Acad Sci USA 94:1878–1883

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Nelson BH, Lord JD, Greenberg PD (1996) A membrane-proximal region of the interleukin-2 receptor γc chain sufficient for Jak kinase activation and induction of proliferation in T cells. Mol Cell Biol 16:309–317

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Nakamura Y, Russell SM, Mess SA, Friedmann M, Erdos M, Francois C, Jacques Y, Adelstein S, Leonard WJ (1994) Heterodimerization of the IL-2 receptor β- and γ-chain cytoplasmic domains is required for signalling. Nature 369:330–333

    Article  PubMed  CAS  Google Scholar 

  98. Durum SK (2014) IL-7 and TSLP receptors: twisted sisters. Blood 124:4–5

    Article  PubMed  CAS  Google Scholar 

  99. Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, Tritapoe J, Hixon JA, Silveira AB, Cardoso BA, Sarmento LM, Correia N, Toribio ML, Kobarg J, Horstmann M, Pieters R, Brandalise SR, Ferrando AA, Meijerink JP, Durum SK, Yunes JA, Barata JT (2011) Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat Genet 43:932–939

    Article  PubMed  CAS  Google Scholar 

  100. Shochat C, Tal N, Gryshkova V, Birger Y, Bandapalli OR, Cazzaniga G, Gershman N, Kulozik AE, Biondi A, Mansour MR, Twizere JC, Muckenthaler MU, Ben-Tal N, Constantinescu SN, Bercovich D, Izraeli S (2014) Novel activating mutations lacking cysteine in type I cytokine receptors in acute lymphoblastic leukemia. Blood 124:106–110

    Article  PubMed  CAS  Google Scholar 

  101. Tsujino S, Di Santo JP, Takaoka A, McKernan TL, Noguchi S, Taya C, Yonekawa H, Saito T, Taniguchi T, Fujii H (2000) Differential requirement of the cytoplasmic subregions of γc chain in T cell development and function. Proc Natl Acad Sci USA 97:10514–10519

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Goldsmith MA, Lai SY, Xu W, Amaral MC, Kuczek ES, Parent LJ, Mills GB, Tarr KL, Longmore GD, Greene WC (1995) Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the β chain and non-tyrosine residues of the γc chain. J Biol Chem 270:21729–21737

    Article  PubMed  CAS  Google Scholar 

  103. Asao H, Kumaki S, Takeshita T, Nakamura M, Sugamura K (1992) IL-2-dependent in vivo and in vitro tyrosine phosphorylation of IL-2 receptor γ chain. FEBS Lett 304:141–145

    Article  PubMed  CAS  Google Scholar 

  104. Lindemann MJ, Benczik M, Gaffen SL (2003) Anti-apoptotic signaling by the interleukin-2 receptor reveals a function for cytoplasmic tyrosine residues within the common γ (γc) receptor subunit. J Biol Chem 278:10239–10249

    Article  PubMed  CAS  Google Scholar 

  105. Kobayashi N, Nakagawa S, Minami Y, Taniguchi T, Kono T (1993) Cloning and sequencing of the cDNA encoding a mouse IL-2 receptor γ. Gene 130:303–304

    Article  PubMed  CAS  Google Scholar 

  106. Jameson SC, Renkema KR (2014) An uncommon tail about the common γ-chain. Immunity 40:859–860

    Article  PubMed  CAS  Google Scholar 

  107. Levine SJ (2004) Mechanisms of soluble cytokine receptor generation. J Immunol 173:5343–5348

    Article  PubMed  CAS  Google Scholar 

  108. Rubin LA, Kurman CC, Fritz ME, Biddison WE, Boutin B, Yarchoan R, Nelson DL (1985) Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol 135:3172–3177

    PubMed  CAS  Google Scholar 

  109. Holter W, Goldman CK, Casabo L, Nelson DL, Greene WC, Waldmann TA (1987) Expression of functional IL 2 receptors by lipopolysaccharide and interferon-γ stimulated human monocytes. J Immunol 138:2917–2922

    PubMed  CAS  Google Scholar 

  110. Honda M, Kitamura K, Takeshita T, Sugamura K, Tokunaga T (1990) Identification of a soluble IL-2 receptor β-chain from human lymphoid cell line cells. J Immunol 145:4131–4135

    PubMed  CAS  Google Scholar 

  111. Idzerda RL, March CJ, Mosley B, Lyman SD, Vanden Bos T, Gimpel SD, Din WS, Grabstein KH, Widmer MB, Park LS et al (1990) Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily. J Exp Med 171:861–873

    Article  PubMed  CAS  Google Scholar 

  112. Goodwin RG, Friend D, Ziegler SF, Jerzy R, Falk BA, Gimpel S, Cosman D, Dower SK, March CJ, Namen AE et al (1990) Cloning of the human and murine interleukin-7 receptors: demonstration of a soluble form and homology to a new receptor superfamily. Cell 60:941–951

    Article  PubMed  CAS  Google Scholar 

  113. Renauld JC, Druez C, Kermouni A, Houssiau F, Uyttenhove C, Van Roost E, Van Snick J (1992) Expression cloning of the murine and human interleukin 9 receptor cDNAs. Proc Natl Acad Sci USA 89:5690–5694

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  114. Mortier E, Bernard J, Plet A, Jacques Y (2004) Natural, proteolytic release of a soluble form of human IL-15 receptor α-chain that behaves as a specific, high affinity IL-15 antagonist. J Immunol 173:1681–1688

    Article  PubMed  CAS  Google Scholar 

  115. Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, Chertova E, Rosenberg SA, Felber BK, Pavlakis GN (2012) Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum. Blood 120:e1–e8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  116. Spangler JB, Moraga I, Mendoza JL, Garcia KC (2015) Insights into cytokine-receptor interactions from cytokine engineering. Annu Rev Immunol 33:139–167

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Wang X, Rickert M, Garcia KC (2005) Structure of the quaternary complex of interleukin-2 with its α, β, and γc receptors. Science 310:1159–1163

    Article  PubMed  CAS  Google Scholar 

  118. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA (2006) Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc Natl Acad Sci USA 103:2788–2793

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  119. Olosz F, Malek TR (2000) Three loops of the common γ chain ectodomain required for the binding of interleukin-2 and interleukin-7. J Biol Chem 275:30100–30105

    Article  PubMed  CAS  Google Scholar 

  120. Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC (2004) Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its α, β, and γc receptors. J Mol Biol 339:1115–1128

    Article  PubMed  CAS  Google Scholar 

  121. Shimizu A, Kondo S, Sabe H, Ishida N, Honjo T (1986) Structure and function of the interleukin 2 receptor: affinity conversion model. Immunol Rev 92:103–120

    Article  PubMed  CAS  Google Scholar 

  122. Liparoto SF, Myszka DG, Wu Z, Goldstein B, Laue TM, Ciardelli TL (2002) Analysis of the role of the interleukin-2 receptor γ chain in ligand binding. Biochemistry 41:2543–2551

    Article  PubMed  CAS  Google Scholar 

  123. Damjanovich S, Bene L, Matko J, Alileche A, Goldman CK, Sharrow S, Waldmann TA (1997) Preassembly of interleukin 2 (IL-2) receptor subunits on resting Kit 225 K6 T cells and their modulation by IL-2, IL-7, and IL-15: a fluorescence resonance energy transfer study. Proc Natl Acad Sci USA 94:13134–13139

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  124. Malka Y, Hornakova T, Royer Y, Knoops L, Renauld JC, Constantinescu SN, Henis YI (2008) Ligand-independent homomeric and heteromeric complexes between interleukin-2 or -9 receptor subunits and the γ chain. J Biol Chem 283:33569–33577

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  125. Pillet AH, Juffroy O, Mazard-Pasquier V, Moreau JL, Gesbert F, Chastagner P, Colle JH, Theze J, Rose T (2008) Human IL-2Rβ chains form IL-2 binding homodimers. Eur Cytokine Netw 19:49–59

    PubMed  CAS  Google Scholar 

  126. Rose T, Pillet AH, Lavergne V, Tamarit B, Lenormand P, Rousselle JC, Namane A, Theze J (2010) Interleukin-7 compartmentalizes its receptor signaling complex to initiate CD4 T lymphocyte response. J Biol Chem 285:14898–14908

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  127. Basu R, Hatton RD, Weaver CT (2013) The Th17 family: flexibility follows function. Immunol Rev 252:89–103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L, Shevach EM, O’Shea JJ (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    Article  PubMed  CAS  Google Scholar 

  129. Rangachari M, Kuchroo VK (2013) Using EAE to better understand principles of immune function and autoimmune pathology. J Autoimmun 45:31–39

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  130. Nielsen OH, Kirman I, Johnson K, Giedlin M, Ciardelli T (1998) The circulating common γ chain (CD132) in inflammatory bowel disease. Am J Gastroenterol 93:323–328

    Article  PubMed  CAS  Google Scholar 

  131. Nishio J, Kohsaka H, Shimamura T, Hamuro J, Miyasaka N (2001) Abundant expression of common cytokine receptor γ chain (CD132) in rheumatoid joints. J Rheumatol 28:240–244

    PubMed  CAS  Google Scholar 

  132. Meissner U, Blum H, Schnare M, Rollinghoff M, Gessner A (2001) A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling. Blood 97:183–191

    Article  PubMed  CAS  Google Scholar 

  133. Hoyer KK, Dooms H, Barron L, Abbas AK (2008) Interleukin-2 in the development and control of inflammatory disease. Immunol Rev 226:19–28

    Article  PubMed  CAS  Google Scholar 

  134. Ouyang W, Kolls JK, Zheng Y (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454–467

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  135. Voss SD, Leary TP, Sondel PM, Robb RJ (1993) Identification of a direct interaction between interleukin 2 and the p64 interleukin 2 receptor γ chain. Proc Natl Acad Sci USA 90:2428–2432

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  136. Schnyder B, Lugli S, Feng N, Etter H, Lutz RA, Ryffel B, Sugamura K, Wunderli-Allenspach H, Moser R (1996) Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common γ chain. Blood 87:4286–4295

    PubMed  CAS  Google Scholar 

  137. Chomarat P, Banchereau J (1998) Interleukin-4 and interleukin-13: their similarities and discrepancies. Int Rev Immunol 17:1–52

    Article  PubMed  CAS  Google Scholar 

  138. Park LS, Martin U, Garka K, Gliniak B, Di Santo JP, Muller W, Largaespada DA, Copeland NG, Jenkins NA, Farr AG, Ziegler SF, Morrissey PJ, Paxton R, Sims JE (2000) Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med 192:659–670

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  139. Al-Shami A, Spolski R, Kelly J, Fry T, Schwartzberg PL, Pandey A, Mackall CL, Leonard WJ (2004) A role for thymic stromal lymphopoietin in CD4+ T cell development. J Exp Med 200:159–168

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  140. Hechinger AK, Smith BA, Flynn R, Hanke K, McDonald-Hyman C, Taylor PA, Pfeifer D, Hackanson B, Leonhardt F, Prinz G, Dierbach H, Schmitt-Graeff A, Kovarik J, Blazar BR, Zeiser R (2015) Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD. Blood 125:570–580

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Drs. Alfred Singer and Xuguang Tai for critical review of this manuscript. We also thank Douglas Joubert, NIH Library Writing Center, for manuscript editing assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jung-Hyun Park.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waickman, A.T., Park, JY. & Park, JH. The common γ-chain cytokine receptor: tricks-and-treats for T cells. Cell. Mol. Life Sci. 73, 253–269 (2016). https://doi.org/10.1007/s00018-015-2062-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-2062-4

Keywords

Navigation