Anat Cell Biol.  2015 Mar;48(1):10-15. 10.5115/acb.2015.48.1.10.

The role of soluble common gamma chain in autoimmune disease

Affiliations
  • 1Department of Anatomy, Pusan National University School of Medicine, Yangsan, Korea. chong@pusan.ac.kr

Abstract

The common gamma chain (gammac) is the central signaling unit for a number of cytokine receptors collectively known as the gammac cytokine receptor family. gammac is critical for ligand binding and signaling by gammac cytokines. gammac cytokine signaling had been thought to be mainly regulated by cytokine-specific receptor alpha chain expression levels with little or no effect by gammac surface levels because gammac expression was presumed to remain unchanged during T-cell activation and development. The extent of gammac cytokine responses is thought to be regulated by cytokine specific receptor subunits and not by the gammac receptor. In contrast to this prevailing view, we have recently reported that gammac itself actively regulates gammac cytokine responses. Interestingly, gammac exerted its regulatory effects not only as a conventional membrane receptor protein but also as a secreted protein whose expression was upregulated upon T-cell stimulation. Here we will review how a soluble form of gammac, which is generated by alternative splicing, regulates gammac cytokine signaling and plays a role in controlling immune activation related to autoimmune disease.

Keyword

Common gamma chain; Autoimmune disease; Cytokine; Soluble receptors

MeSH Terms

Alternative Splicing
Autoimmune Diseases*
Cytokines
Humans
Membranes
Receptors, Cytokine
T-Lymphocytes
Cytokines
Receptors, Cytokine

Figure

  • Fig. 1 Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway of gamma chain (γc) family cytokines. The trans-activation of JAKs after cytokine stimulation results in the phosphorylation of STATs, which then dimerize and translocate to the nucleus to activate gene transcription.

  • Fig. 2 Inhibitory function of soluble gamma chain (sγc) generated by alternative splicing in cytokine signaling. Activated T cells upregulate expression of an alternatively spliced form of gamma chain (γc) mRNA. γc splice isoform expression results in secretion of the γc extracellular domain. Soluble γc binds directly to surface interleukin (IL)-2Rβ and inhibits IL-2 signaling.


Reference

1. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009; 9:480–490.
2. Leonard WJ. Cytokines and immunodeficiency diseases. Nat Rev Immunol. 2001; 1:200–208.
3. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol. 1998; 16:293–322.
4. Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S, Leonard WJ. The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity. 1995; 2:331–339.
5. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994; 265:1701–1706.
6. Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM, Cleveland JL, Pierce JH, Keegan AD, Nelms K, Paul WE, Ihle JN. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol. 1995; 15:3336–3343.
7. Ozaki K, Kikly K, Michalovich D, Young PR, Leonard WJ. Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci U S A. 2000; 97:11439–11444.
8. Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature. 2000; 408:57–63.
9. Fischer A, Hacein-Bey S, Le Deist F, de Saint Basile G, Cavazzana-Calvo M. Gene therapy for human severe combined immunodeficiencies. Isr Med Assoc J. 2002; 4:51–54.
10. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S, Modi WS, McBride OW, Leonard WJ. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell. 1993; 73:147–157.
11. Levine SJ. Mechanisms of soluble cytokine receptor generation. J Immunol. 2004; 173:5343–5348.
12. Heaney ML, Golde DW. Soluble cytokine receptors. Blood. 1996; 87:847–857.
13. Fernandez-Botran R. Soluble cytokine receptors: their role in immunoregulation. FASEB J. 1991; 5:2567–2574.
14. Levine SJ. Molecular mechanisms of soluble cytokine receptor generation. J Biol Chem. 2008; 283:14177–14181.
15. Meissner U, Blum H, Schnare M, Röllinghoff M, Gessner A. A soluble form of the murine common gamma chain is present at high concentrations in vivo and suppresses cytokine signaling. Blood. 2001; 97:183–191.
16. Lundstrom W, Highfill S, Walsh ST, Beq S, Morse E, Kockum I, Alfredsson L, Olsson T, Hillert J, Mackall CL. Soluble IL7Ralpha potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A. 2013; 110:E1761–E1770.
17. Hong C, Luckey MA, Park JH. Intrathymic IL-7: the where, when, and why of IL-7 signaling during T cell development. Semin Immunol. 2012; 24:151–158.
18. Adoro S, Erman B, Sarafova SD, Van Laethem F, Park JH, Feigenbaum L, Singer A. Targeting CD4 coreceptor expression to postselection thymocytes reveals that CD4/CD8 lineage choice is neither error-prone nor stochastic. J Immunol. 2008; 181:6975–6983.
19. Park JH, Adoro S, Lucas PJ, Sarafova SD, Alag AS, Doan LL, Erman B, Liu X, Ellmeier W, Bosselut R, Feigenbaum L, Singer A. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat Immunol. 2007; 8:1049–1059.
20. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007; 7:454–465.
21. Singer A, Adoro S, Park JH. Lineage fate and intense debate: myths, models and mechanisms of CD4-versus CD8-lineage choice. Nat Rev Immunol. 2008; 8:788–801.
22. Fernandez-Botran R, Chilton PM, Ma Y. Soluble cytokine receptors: their roles in immunoregulation, disease, and therapy. Adv Immunol. 1996; 63:269–336.
23. Fernandez-Botran R, Vitetta ES. Evidence that natural murine soluble interleukin 4 receptors may act as transport proteins. J Exp Med. 1991; 174:673–681.
24. Gessner A, Schröppel K, Will A, Enssle KH, Lauffer L, Röllinghoff M. Recombinant soluble interleukin-4 (IL-4) receptor acts as an antagonist of IL-4 in murine cutaneous Leishmaniasis. Infect Immun. 1994; 62:4112–4117.
25. Heaney ML, Golde DW. Soluble receptors in human disease. J Leukoc Biol. 1998; 64:135–146.
26. Novick D, Shulman LM, Chen L, Revel M. Enhancement of interleukin 6 cytostatic effect on human breast carcinoma cells by soluble IL-6 receptor from urine and reversion by monoclonal antibody. Cytokine. 1992; 4:6–11.
27. Rose-John S, Heinrich PC. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J. 1994; 300(Pt 2):281–290.
28. Althoff K, Reddy P, Voltz N, Rose-John S, Müllberg J. Shedding of interleukin-6 receptor and tumor necrosis factor alpha. Contribution of the stalk sequence to the cleavage pattern of transmembrane proteins. Eur J Biochem. 2000; 267:2624–2631.
29. Hughes DP, Crispe IN. A naturally occurring soluble isoform of murine Fas generated by alternative splicing. J Exp Med. 1995; 182:1395–1401.
30. Jensen LE, Muzio M, Mantovani A, Whitehead AS. IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein. J Immunol. 2000; 164:5277–5286.
31. Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine. 1992; 4:96–100.
32. Michel J, Langstein J, Hofstädter F, Schwarz H. A soluble form of CD137 (ILA/4-1BB), a member of the TNF receptor family, is released by activated lymphocytes and is detectable in sera of patients with rheumatoid arthritis. Eur J Immunol. 1998; 28:290–295.
33. Mosley B, Beckmann MP, March CJ, Idzerda RL, Gimpel SD, VandenBos T, Friend D, Alpert A, Anderson D, Jackson J, Wignall JM, Smith C, Gallis B, Sims JE, Urdal D, Widmer MB, Cosman D, Park LS. The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell. 1989; 59:335–348.
34. Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA. An essential role for ectodomain shedding in mammalian development. Science. 1998; 282:1281–1284.
35. Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem. 2000; 275:14608–14614.
36. 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. Activated T cells secrete an alternatively spliced form of common gamma-chain that inhibits cytokine signaling and exacerbates inflammation. Immunity. 2014; 40:910–923.
37. Depper JM, Leonard WJ, Drogula C, Kronke M, Waldmann TA, Greene WC. Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene. Proc Natl Acad Sci U S A. 1985; 82:4230–4234.
38. Siegel JP, Sharon M, Smith PL, Leonard WJ. The IL-2 receptor beta chain (p70): role in mediating signals for LAK, NK, and proliferative activities. Science. 1987; 238:75–78.
39. Park JH, Yu Q, Erman B, Appelbaum JS, Montoya-Durango D, Grimes HL, Singer A. Suppression of IL7Ralpha transcription by IL-7 and other prosurvival cytokines: a novel mechanism for maximizing IL-7-dependent T cell survival. Immunity. 2004; 21:289–302.
40. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994; 370:151–153.
41. 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. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007; 26:371–381.
42. Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio CW, Vegoe AL, Hsieh CS, Jenkins MK, Farrar MA. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008; 28:112–121.
43. Nielsen OH, Kirman I, Johnson K, Giedlin M, Ciardelli T. The circulating common gamma chain (CD132) in inflammatory bowel disease. Am J Gastroenterol. 1998; 93:323–328.
44. Nishio J, Kohsaka H, Shimamura T, Hamuro J, Miyasaka N. Abundant expression of common cytokine receptor gamma chain (CD132) in rheumatoid joints. J Rheumatol. 2001; 28:240–244.
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