Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation

Abstract

Transcription factors of the STAT family are critical in the cytokine-mediated functional differentiation of CD4+ helper T cells. Signaling inhibitors of the SOCS family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by directly binding to the Il9 promoter. Our data thus demonstrate a critical role for CIS in controlling the proallergic generation of helper T cells.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Expression and signaling function of CIS.
Figure 2: CIS deficiency leads to spontaneous pulmonary disease.
Figure 3: CIS negatively regulates allergic asthma responses.
Figure 4: CD4+ T cell–specific Cis deletion leads to enhanced allergic asthma disease.
Figure 5: CIS function in helper T cell differentiation.
Figure 6: Enhanced TH9 differentiation in the absence of CIS.
Figure 7: CIS controls TH9 differentiation by modulating the activity of STAT5 and STAT6.

Similar content being viewed by others

References

  1. Dong, C. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat. Rev. Immunol. 6, 329–333 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Glimcher, L.H. & Murphy, K.M. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev. 14, 1693–1711 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Dong, C. & Flavell, R.A. Control of T helper cell differentiation–in search of master genes. Sci. STKE 2000, PE1 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Cote-Sierra, J. et al. Interleukin 2 plays a central role in Th2 differentiation. Proc. Natl. Acad. Sci. USA 101, 3880–3885 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yamane, H., Zhu, J. & Paul, W.E. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. J. Exp. Med. 202, 793–804 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Liao, W. et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor α-chain expression. Nat. Immunol. 9, 1288–1296 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dong, C. Differentiation and function of pro-inflammatory Th17 cells. Microbes Infect. 11, 584–588 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Schmitt, E. et al. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-β and IL-4, and is inhibited by IFN-β. J. Immunol. 153, 3989–3996 (1994).

    CAS  PubMed  Google Scholar 

  10. Dardalhon, V. et al. IL-4 inhibits TGF-β-induced Foxp3+ T cells and, together with TGF-β, generates IL-9+IL-10+Foxp3 effector T cells. Nat. Immunol. 9, 1347–1355 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Veldhoen, M. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. O'Shea, J.J., Gadina, M. & Schreiber, R.D. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109 (suppl.), S121–S131 (2002).

    Article  CAS  PubMed  Google Scholar 

  13. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7, 454–465 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Palmer, D.C. & Restifo, N.P. Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends Immunol. 30, 592–602 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, J.G. et al. The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action in vivo. Proc. Natl. Acad. Sci. USA 98, 13261–13265 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yoshimura, A. et al. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 14, 2816–2826 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sakamoto, H. et al. A Janus kinase inhibitor, JAB, is an interferon-γ-inducible gene and confers resistance to interferons. Blood 92, 1668–1676 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Alexander, W.S. et al. SOCS1 is a critical inhibitor of interferon γ signaling and prevents the potentially fatal neonatal actions of this cytokine. Cell 98, 597–608 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Eyles, J.L., Metcalf, D., Grusby, M.J., Hilton, D.J. & Starr, R. Negative regulation of interleukin-12 signaling by suppressor of cytokine signaling-1. J. Biol. Chem. 277, 43735–43740 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Diehl, S. et al. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805–815 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Egwuagu, C.E. et al. Suppressors of cytokine signaling proteins are differentially expressed in Th1 and Th2 cells: implications for Th cell lineage commitment and maintenance. J. Immunol. 168, 3181–3187 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Kubo, M. & Inoue, H. Suppressor of cytokine signaling 3 (SOCS3) in Th2 cells evokes Th2 cytokines, IgE, and eosinophilia. Curr. Allergy Asthma Rep. 6, 32–39 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Seki, Y. et al. SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nat. Med. 9, 1047–1054 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Kubo, M., Ozaki, A., Tanaka, S., Okamoto, M. & Fukushima, A. Role of suppressor of cytokine signaling in ocular allergy. Curr. Opin. Allergy Clin. Immunol. 6, 361–366 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Kinjyo, I. et al. Loss of SOCS3 in T helper cells resulted in reduced immune responses and hyperproduction of interleukin 10 and transforming growth factor-β 1. J. Exp. Med. 203, 1021–1031 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chen, Z. et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc. Natl. Acad. Sci. USA 103, 8137–8142 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ogura, H. et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity 29, 628–636 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Seki, Y. et al. Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc. Natl. Acad. Sci. USA 99, 13003–13008 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Brender, C. et al. SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol. Cell Biol. 24, 6094–6103 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Iwatsuki, K. et al. STAT5 Activation correlates with erythropoietin receptor-mediated erythroid differentiation of an erythroleukemia cell line. J. Biol. Chem. 272, 8149–8152 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Ram, P.A. & Waxman, D.J. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J. Biol. Chem. 274, 35553–35561 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Matsumoto, A. et al. CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 89, 3148–3154 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Aman, M.J. et al. CIS associates with the interleukin-2 receptor β chain and inhibits interleukin-2-dependent signaling. J. Biol. Chem. 274, 30266–30272 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Yang, X.O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Laouini, D. et al. IL-10 is critical for Th2 responses in a murine model of allergic dermatitis. J. Clin. Invest. 112, 1058–1066 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Temann, U.A., Geba, G.P., Rankin, J.A. & Flavell, R.A. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188, 1307–1320 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. McLane, M.P. et al. Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. Am. J. Respir. Cell Mol. Biol. 19, 713–720 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Ying, S., Meng, Q., Kay, A.B. & Robinson, D.S. Elevated expression of interleukin-9 mRNA in the bronchial mucosa of atopic asthmatics and allergen-induced cutaneous late-phase reaction: relationships to eosinophils, mast cells and T lymphocytes. Clin. Exp. Allergy 32, 866–871 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Onishi, M. et al. Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol. Cell Biol. 18, 3871–3879 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Goswami, R. et al. STAT6-dependent regulation of Th9 development. J. Immunol. 188, 968–975 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Zhu, J., Cote-Sierra, J., Guo, L. & Paul, W.E. Stat5 activation plays a critical role in Th2 differentiation. Immunity 19, 739–748 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Scheinman, E.J. & Avni, O. Transcriptional regulation of GATA3 in T helper cells by the integrated activities of transcription factors downstream of the interleukin-4 receptor and T cell receptor. J. Biol. Chem. 284, 3037–3048 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Ovcharenko, I., Nobrega, M.A., Loots, G.G. & Stubbs, L. ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes. Nucleic Acids Res. 32, W280–W286 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Loots, G.G. & Ovcharenko, I. rVISTA 2.0: evolutionary analysis of transcription factor binding sites. Nucleic Acids Res. 32, W217–W221 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Chang, H.C. et al. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat. Immunol. 11, 527–534 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Staudt, V. et al. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33, 192–202 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Kasaian, M.T. & Miller, D.K. IL-13 as a therapeutic target for respiratory disease. Biochem. Pharmacol. 76, 147–155 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Wynn, T.A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Doherty, T. & Broide, D. Cytokines and growth factors in airway remodeling in asthma. Curr. Opin. Immunol. 19, 676–680 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Temann, U.A., Laouar, Y., Eynon, E.E., Homer, R. & Flavell, R.A. IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells. Int. Immunol. 19, 1–10 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Spits, H. & Di Santo, J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat. Immunol. 12, 21–27 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Lee, P.P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

    CAS  PubMed  Google Scholar 

  54. Rubtsov, Y.P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Dai, X. et al. Stat5 is essential for early B cell development but not for B cell maturation and function. J. Immunol. 179, 1068–1079 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Fu, G. et al. Phospholipase Cγ1 is essential for T cell development, activation, and tolerance. J. Exp. Med. 207, 309–318 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Hwang, E.S., White, I.A. & Ho, I.C. An IL-4-independent and CD25-mediated function of c-maf in promoting the production of Th2 cytokines. Proc. Natl. Acad. Sci. USA 99, 13026–13030 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Angkasekwinai, P., Chang, S.H., Thapa, M., Watarai, H. & Dong, C. Regulation of IL-9 expression by IL-25 signaling. Nat. Immunol. 11, 250–256 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lang, R., Rutschman, R.L., Greaves, D.R. & Murray, P.J. Autocrine deactivation of macrophages in transgenic mice constitutively overexpressing IL-10 under control of the human CD68 promoter. J. Immunol. 168, 3402–3411 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Yang, X.O. et al. Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment. Nat. Immunol. 10, 1260–1266 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Voice, J. et al. c-Maf and JunB mediation of Th2 differentiation induced by the type 2 G protein-coupled receptor (VPAC2) for vasoactive intestinal peptide. J. Immunol. 172, 7289–7296 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Evans, K.E. & Fox, S.W. Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus. BMC Cell Biol. 8, 4 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Yang, X.O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J. Biol. Chem. 282, 9358–9363 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Yang, X.O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Bruns, H.A., Schindler, U. & Kaplan, M.H. Expression of a constitutively active Stat6 in vivo alters lymphocyte homeostasis with distinct effects in T and B cells. J. Immunol. 170, 3478–3487 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Rivera and J. Parker-Thornburg of the MD Anderson Genetic Engineered Mouse Facility for help in generating gene-targeted mice; A.Y. Rudensky (Memorial Sloan-Kettering Cancer Center) for Foxp3-GFP and Foxp3-Cre mice; C.B. Wilson (University of Washington) for CD4-Cre mice; M. Kaplan (Indiana University School of Medicine) for the STAT6VT-expressing construct; and members of the Dong laboratory for help and discussion. Supported by the US National Institutes of Health (C.D., S.S.W., D.W. and D.B.C.), the Leukemia and Lymphoma Society (C.D. and D.W.), MD Anderson Cancer Center (C.D.), the Biology of Inflammation Center at Baylor College of Medicine (D.B.C.), the American Heart Association, the American Cancer Society (X.O.Y.), the Shanghai Board of Health Foundation, Shanghai Jiao Tong University (X.N.) and the Ministry of Education of China (J.P.).

Author information

Authors and Affiliations

Authors

Contributions

C.D. and X.O.Y. conceived of the project, designed the experiments and wrote the manuscript; X.O.Y., H.Z. and B.-S.K. did most of the experiments; and X.N., J.P., Y.C., R.K., Y.-H.L., S.H.C., D.B.C., D.W. and S.S.W. participated in specific experiments.

Corresponding authors

Correspondence to Xuexian O Yang or Chen Dong.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 (PDF 1119 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, X., Zhang, H., Kim, BS. et al. The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat Immunol 14, 732–740 (2013). https://doi.org/10.1038/ni.2633

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2633

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing