[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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:

Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5

Nature Immunology volume 12, pages 247–254 (2011)Cite this article

Subjects

Abstract

Interleukin 2 (IL-2), a cytokine linked to human autoimmune disease, limits IL-17 production. Here we found that deletion of the gene encoding the transcription factor STAT3 in T cells abrogated IL-17 production and attenuated autoimmunity associated with IL-2 deficiency. Whereas STAT3 induced IL-17 and the transcription factor RORγt and inhibited the transcription factor Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. STAT3 and STAT5 bound to multiple common sites across the locus encoding IL-17. The induction of STAT5 binding by IL-2 was associated with less binding of STAT3 at these sites and the inhibition of associated active epigenetic marks. 'Titration' of the relative activation of STAT3 and STAT5 modulated the specification of cells to the IL-17-producing helper T cell (TH17 cell) subset. Thus, the balance rather than the absolute magnitude of these signals determined the propensity of cells to make a key inflammatory cytokine.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: The inflammatory colitis in IL-2 deficient mice is dependent on STAT3 in T cells.
Figure 2: IL-2 inhibits IL-17A expression in the absence of Foxp3.
Figure 3: Overexpression of RORγt does not abrogate the inhibitory effect of IL-2.
Figure 4: STAT3 and STAT5 compete for the same binding sites in the Il17a–Il17f locus.
Figure 5: STAT5 binding is associated with fewer active epigenetic marks across the Il17a promoter region and associated enhancer elements.
Figure 6: The generation of TH17 cells is dynamically regulated by opposing effects of IL-2 and IL-6: differences in the regulation of IL-17A and IL-17F.

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Weaver, C.T. & Hatton, R.D. Interplay between the TH17 and TReg cell lineages: a (co-)evolutionary perspective. Nat. Rev. Immunol. 9, 883–889 (2009).

    Article  CAS  Google Scholar 

  2. Zhu, J., Yamane, H. & Paul, W.E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010).

    Article  CAS  Google Scholar 

  3. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    Article  CAS  Google Scholar 

  4. Hsu, H.C. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166–175 (2008).

    Article  CAS  Google Scholar 

  5. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  Google Scholar 

  6. Bettelli, E., Korn, T. & Kuchroo, V.K. Th17: the third member of the effector T cell trilogy. Curr. Opin. Immunol. 19, 652–657 (2007).

    Article  CAS  Google Scholar 

  7. Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  8. Ghoreschi, K. et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature 467, 967–971 (2010).

    Article  CAS  Google Scholar 

  9. 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  Google Scholar 

  10. Durant, L. et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32, 605–615 (2010).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. Mathur, A.N. et al. Stat3 and Stat4 direct development of IL-17-secreting Th cells. J. Immunol. 178, 4901–4907 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Harris, T.J. et al. Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J. Immunol. 179, 4313–4317 (2007).

    Article  CAS  Google Scholar 

  15. Milner, J.D. et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).

    Article  CAS  Google Scholar 

  16. Cenit, M.C. et al. STAT3 locus in inflammatory bowel disease and multiple sclerosis susceptibility. Genes Immun. 11, 264–268 (2010).

    Article  CAS  Google Scholar 

  17. Stumhofer, J.S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006).

    Article  CAS  Google Scholar 

  18. Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).

    Article  CAS  Google Scholar 

  19. Elias, K.M. et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111, 1013–1020 (2008).

    Article  CAS  Google Scholar 

  20. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  Google Scholar 

  21. Moriggl, R. et al. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10, 249–259 (1999).

    Article  CAS  Google Scholar 

  22. Malek, T.R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).

    Article  CAS  Google Scholar 

  23. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 6, 345–352 (2005).

    Article  CAS  Google Scholar 

  24. Yao, Z. et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109, 4368–4375 (2007).

    Article  CAS  Google Scholar 

  25. Diveu, C. et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182, 5748–5756 (2009).

    Article  CAS  Google Scholar 

  26. Wong, P.K. et al. SOCS-3 negatively regulates innate and adaptive immune mechanisms in acute IL-1-dependent inflammatory arthritis. J. Clin. Invest. 116, 1571–1581 (2006).

    Article  CAS  Google Scholar 

  27. Mukasa, R. et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity 32, 616–627 (2010).

    Article  CAS  Google Scholar 

  28. Akimzhanov, A.M., Yang, X.O. & Dong, C. Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J. Biol. Chem. 282, 5969–5972 (2007).

    Article  CAS  Google Scholar 

  29. Visel, A. et al. ChIP-seq accurately predicts tissue-specific activity of enhancers. Nature 457, 854–858 (2009).

    Article  CAS  Google Scholar 

  30. Heintzman, N.D. et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat. Genet. 39, 311–318 (2007).

    Article  CAS  Google Scholar 

  31. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).

    Article  Google Scholar 

  32. Nakajima, H., Brindle, P.K., Handa, M. & Ihle, J.N. Functional interaction of STAT5 and nuclear receptor co-repressor SMRT: implications in negative regulation of STAT5-dependent transcription. EMBO J. 20, 6836–6844 (2001).

    Article  CAS  Google Scholar 

  33. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  Google Scholar 

  34. Sadlack, B. et al. Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053–3059 (1995).

    Article  CAS  Google Scholar 

  35. Sharfe, N., Dadi, H.K., Shahar, M. & Roifman, C.M. Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc. Natl. Acad. Sci. USA 94, 3168–3171 (1997).

    Article  CAS  Google Scholar 

  36. Cohen, A.C. et al. Cutting edge: Decreased accumulation and regulatory function of CD4+CD25high T cells in human STAT5b deficiency. J. Immunol. 177, 2770–2774 (2006).

    Article  CAS  Google Scholar 

  37. Hafler, D.A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

    Article  CAS  Google Scholar 

  38. Lowe, C.E. et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat. Genet. 39, 1074–1082 (2007).

    Article  CAS  Google Scholar 

  39. Hoyer, K.K., Kuswanto, W.F., Gallo, E. & Abbas, A.K. Distinct roles of helper T-cell subsets in a systemic autoimmune disease. Blood 113, 389–395 (2009).

    Article  CAS  Google Scholar 

  40. Park, J.H. et al. 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 (2010).

    Article  CAS  Google Scholar 

  41. Wei, L. et al. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity 32, 840–851 (2010).

    Article  CAS  Google Scholar 

  42. Esashi, E. et al. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 28, 509–520 (2008).

    Article  CAS  Google Scholar 

  43. Yu, M. et al. Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis. Mol. Cell 36, 682–695 (2009).

    Article  CAS  Google Scholar 

  44. Walker, S.R. et al. Reciprocal effects of STAT5 and STAT3 in breast cancer. Mol. Cancer Res. 7, 966–976 (2009).

    Article  CAS  Google Scholar 

  45. Rayman, J.B. et al. E2F mediates cell cycle-dependent transcriptional repression in vivo by recruitment of an HDAC1/mSin3B corepressor complex. Genes Dev. 16, 933–947 (2002).

    Article  CAS  Google Scholar 

  46. Wells, J., Boyd, K.E., Fry, C.J., Bartley, S.M. & Farnham, P.J. Target gene specificity of E2F and pocket protein family members in living cells. Mol. Cell. Biol. 20, 5797–5807 (2000).

    Article  CAS  Google Scholar 

  47. Takahashi, Y., Rayman, J.B. & Dynlacht, B.D. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 14, 804–816 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Saccani, S., Pantano, S. & Natoli, G. Modulation of NF-κB activity by exchange of dimers. Mol. Cell 11, 1563–1574 (2003).

    Article  CAS  Google Scholar 

  49. Lee, C.K. et al. STAT3 is a negative regulator of granulopoiesis but is not required for G-CSF-dependent differentiation. Immunity 17, 63–72 (2002).

    Article  CAS  Google Scholar 

  50. Yang, X.O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank J. Simone, J. Lay and the National Institute of Arthritis, Musculoskeletal and Skin Diseases Laboratory Animal Care and Use Section staff for technical support; D. Levy (New York University) for mice with loxP-flanked Stat3 alleles; C. Dong (MD Anderson) for IL-17F–RFP reporter mice; W. Ouyang (Genentech) for monoclonal anti-IL-22; and S. Kuchen, F.C. Eberle and K. Tarbell for comments on the manuscript. Supported by the Intramural Research programs of National Institute of Arthritis, Musculoskeletal and Skin Diseases and National Institute of Allergy and Infectious Diseases.

Author information

Authors and Affiliations

  1. Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Xiang-Ping Yang, Kamran Ghoreschi, Scott M Steward-Tharp, Kiyoshi Hirahara, Hong-Wei Sun, Golnaz Vahedi, Yuka Kanno, John J O'Shea & Arian Laurence

  2. Laser Capture Microdissection Core Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Jaime Rodriguez-Canales

  3. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Jinfang Zhu

  4. Mucosal Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    John R Grainger

  5. Clinical Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA

    Lai Wei

Authors
  1. Xiang-Ping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kamran Ghoreschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott M Steward-Tharp
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jaime Rodriguez-Canales
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jinfang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John R Grainger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kiyoshi Hirahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong-Wei Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lai Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Golnaz Vahedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuka Kanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John J O'Shea
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Arian Laurence
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

X.-P.Y. designed and did experiments, analyzed and wrote the manuscript; K.G. designed and did experiments and helped write the manuscript; S.M.S.-T. helped analyze gut lymphocytes; J.R.-C. examined the histopathology; J.Z., K.H. and J.R.G. provided mice and helped with experiments; Y.K. did ChIP-seq experiments; L.W., H.-W.S., Y.K. and G.V. analyzed data from the ChIP-seq and microarray experiments; J.J.O.'S. designed experiments, analyzed all acquired data and helped write the manuscript; and A.L. designed, did or interpreted all experiments and wrote the manuscript.

Corresponding author

Correspondence to Arian Laurence.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Table 1 (PDF 1187 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, XP., Ghoreschi, K., Steward-Tharp, S. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 12, 247–254 (2011). https://doi.org/10.1038/ni.1995

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1995

This article is cited by

Search

Advanced 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