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TH9 cells that express the transcription factor PU.1 drive T cell–mediated colitis via IL-9 receptor signaling in intestinal epithelial cells

Nature Immunology volume 15, pages 676686 (2014) | Download Citation

  • A Corrigendum to this article was published on 16 January 2015

Abstract

The molecular checkpoints that drive inflammatory bowel diseases are incompletely understood. Here we found more T cells expressing the transcription factor PU.1 and interleukin 9 (IL-9) in patients with ulcerative colitis. In an animal model, citrine reporter mice had more IL-9-expressing mucosal T cells in experimental oxazolone-induced colitis. IL-9 deficiency suppressed acute and chronic colitis. Mice with PU.1 deficiency in T cells were protected from colitis, whereas treatment with antibody to IL-9 suppressed colitis. Functionally, IL-9 impaired intestinal barrier function and prevented mucosal wound healing in vivo. Thus, our findings suggest that the TH9 subset of helper T cells serves an important role in driving ulcerative colitis by regulating intestinal epithelial cells and that TH9 cells represent a likely target for the treatment of chronic intestinal inflammation.

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References

  1. 1.

    New therapies for inflammatory bowel disease: from the bench to the bedside. Gut 61, 918–932 (2012).

  2. 2.

    , & The fundamental basis of inflammatory bowel disease. J. Clin. Invest. 117, 514–521 (2007).

  3. 3.

    & Immunity, inflammation, and allergy in the gut. Science 307, 1920–1925 (2005).

  4. 4.

    & Ulcerative colitis. N. Engl. J. Med. 365, 1713–1725 (2011).

  5. 5.

    , & The role of Th1/Th2 polarization in mucosal immunity. Nat. Med. 8, 567–573 (2002).

  6. 6.

    et al. The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease. J. Exp. Med. 195, 1129–1143 (2002).

  7. 7.

    et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261–1270 (1996).

  8. 8.

    & The role of IL-13 and NK T cells in experimental and human ulcerative colitis. Mucosal Immunol. 1 (suppl. 1), S31–S33 (2008).

  9. 9.

    et al. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease. Gut 57, 1682–1689 (2008).

  10. 10.

    et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525–534 (2009).

  11. 11.

    et al. T-helper 17 and interleukin-17-producing lymphoid tissue inducer-like cells make different contributions to colitis in mice. Gastroenterology 143, 1288–1297 (2012).

  12. 12.

    et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33, 279–288 (2010).

  13. 13.

    et al. RORγ-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 136, 257–267 (2009).

  14. 14.

    , , , & Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13-producing NK-T cells. Immunity 17, 629–638 (2002).

  15. 15.

    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).

  16. 16.

    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).

  17. 17.

    , & Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology 189, 419–435 (1993).

  18. 18.

    et al. Th9 cells drive host immunity against gastrointestinal worm infection. Immunity 39, 744–757 (2013).

  19. 19.

    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).

  20. 20.

    et al. IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation. J. Exp. Med. 210, 2951–2965 (2013).

  21. 21.

    , , , & Regulation of IL-9 expression by IL-25 signaling. Nat. Immunol. 11, 250–256 (2010).

  22. 22.

    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).

  23. 23.

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

  24. 24.

    et al. Th9 cell development requires a BATF-regulated transcriptional network. J. Clin. Invest. 123, 4641–4653 (2013).

  25. 25.

    & Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J. Immunol. 189, 3026–3033 (2012).

  26. 26.

    , & Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J. Clin. Invest. 109, 29–39 (2002).

  27. 27.

    & The symphony of the ninth: the development and function of Th9 cells. Curr. Opin. Immunol. 24, 303–307 (2012).

  28. 28.

    et al. Allergen-induced interleukin-9 production in vitro: correlation with atopy in human adults and comparison with interleukin-5 and interleukin-13. Clin. Exp. Allergy 36, 174–182 (2006).

  29. 29.

    et al. Epithelial tight junctions in intestinal inflammation. Ann. NY Acad. Sci. 1165, 294–300 (2009).

  30. 30.

    , & Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling. Biochem. J. 353, 109–116 (2001).

  31. 31.

    Th9 cells: differentiation and disease. Immunol. Rev. 252, 104–115 (2013).

  32. 32.

    , , , & IL-33 induces IL-9 production in human CD4+ T cells and basophils. PLoS ONE 6, e21695 (2011).

  33. 33.

    , & TGF-beta interactions with IL-1 family members trigger IL-4-independent IL-9 production by mouse CD4+ T cells. Eur. J. Immunol. 40, 2230–2235 (2010).

  34. 34.

    et al. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity 13, 573–583 (2000).

  35. 35.

    & The function role of GATA-3 in Th1 and Th2 differentiation. Immunol. Res. 28, 25–37 (2003).

  36. 36.

    et al. Confocal laser endomicroscopy is a new imaging modality for recognition of intramucosal bacteria in inflammatory bowel disease in vivo. Gut 60, 26–33 (2011).

  37. 37.

    & Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).

  38. 38.

    et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

  39. 39.

    , , & Th17-related cytokines in inflammatory bowel diseases: friends or foes? Curr. Mol. Med. 12, 592–597 (2012).

  40. 40.

    et al. The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J. Clin. Invest. 118, 2415–2426 (2008).

  41. 41.

    et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc. Natl. Acad. Sci. USA 107, 8017–8022 (2010).

  42. 42.

    et al. Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J. Gastroenterol. 45, 999–1007 (2010).

  43. 43.

    et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl. Acad. Sci. USA 106, 12885–12890 (2009).

  44. 44.

    et al. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J. Exp. Med. 205, 897–913 (2008).

  45. 45.

    et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129, 550–564 (2005).

  46. 46.

    & IL-9-producing invariant NKT cells protect against DSS-induced colitis in an IL-4-dependent manner. Mucosal Immunol. 6, 347–357 (2013).

  47. 47.

    , & IL-33 citrine reporter mice reveal the temporal and spatial expression of IL-33 during allergic lung inflammation. Eur. J. Immunol. 43, 488–498 (2013).

  48. 48.

    & DNA damage and repair in epithelial (mucous) cells and crypt cells from isolated colon. Chem. Biol. Interact. 52, 311–318 (1985).

  49. 49.

    et al. CD98 expression modulates intestinal homeostasis, inflammation, and colitis-associated cancer in mice. J. Clin. Invest. 121, 1733–1747 (2011).

  50. 50.

    et al. Transcription factor RORα is critical for nuocyte development. Nat. Immunol. 13, 229–236 (2012).

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Acknowledgements

Supported by the Clinical Research Group CEDER of the German Research Council (B.W., R.A. and M.F.N.), Deutsche Forschungsgemeinschaft (WE 4656/1-1 for support of B.W., R.A. and M.F.N.), Interdisziplinares Zentrum fur Klinische Forschung (B.W., R.A. and M.F.N.), the Emerging Field Initiative (B.W., R.A. and M.F.N.), the ELAN programs of the University Erlangen-Nürnberg (B.W., R.A. and M.F.N.), Deutsche Forschungsgemeinschaft Collaborative Research Centers 643 and 796 (H.D., S.W. and M.F.N.), the American Asthma Foundation, the UK Medical Research Council, the Wellcome Trust (100963 to A.N.J.M.) and the Agency for Science Technology and Research (Y.Y.H.).

Author information

Author notes

    • Benno Weigmann
    •  & Markus F Neurath

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.

    • Katharina Gerlach
    • , Raja Atreya
    • , Heike Dornhoff
    • , Stefanie Steiner
    • , Stefan Wirtz
    • , Benno Weigmann
    •  & Markus F Neurath
  2. MRC Laboratory of Molecular Biology, Cambridge, UK.

    • YouYi Hwang
    •  & Andrew N J McKenzie
  3. Institute of Molecular Medicine, University Medical Center Mainz, Mainz, Germany.

    • Alexej Nikolaev
    •  & Ari Waisman
  4. Institute of Pathology, Campus Bodensee, Friedrichshafen, Germany.

    • Hans-Anton Lehr
  5. Institute of Pathology, Bayreuth Clinic, Bayreuth, Germany.

    • Michael Vieth
  6. Laboratory of Molecular Stem Cell Biology, University of Münster, Münster, Germany.

    • Frank Rosenbauer

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Contributions

K.G. did experiments together with Y.Y.H., A.N., S.S. and B.W.; R.A., H.D., S.W., F.R., A.N.J.M., B.W. and M.F.N. provided clinical samples, protocols or mice or designed experiments; K.G., Y.Y.H., A.N., S.S., H.-A.L., M.V., A.N.J.M. and B.W. analyzed data; K.G., H.-A.L., A.W., F.R., A.N.J.M., B.W. and M.F.N. discussed and interpreted findings; and K.G., Y.Y.H., B.W. and M.F.N. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Markus F Neurath.

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DOI

https://doi.org/10.1038/ni.2920

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