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Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells

Nature Medicine volume 22, pages 319–323 (2016)Cite this article

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Abstract

RAR-related orphan receptor-γt (ROR-γt) directs differentiation of proinflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases1,2,3. However, ROR-γt–dependent group 3 innate lymphoid cells ILC3s provide essential immunity and tissue protection in the intestine4,5,6,7,8,9,10,11, suggesting that targeting ROR-γt could also result in impaired host defense after infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 but not ILCs in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Temporal deletion of Rorc (encoding ROR-γt) in mature ILCs also did not impair cytokine response in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt provided therapeutic benefit in mouse models of intestinal inflammation and reduced the frequency of TH17 cells but not ILCs isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for ROR-γt in the maintenance of TH17 cell and ILC3 responses and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

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Figure 1: Transient chemical inhibition of ROR-γt selectively reduces TH17 responses but not ILC3s in mice infected with C. rodentium.
Figure 2: Transient deletion of ROR-γt impairs TH17 cells but not ILC3s during homeostasis and intestinal infection.
Figure 3: Transient inhibition of ROR-γt selectively limits TH17 cell responses and reduces intestinal inflammation.
Figure 4: Selective reduction of TH17 cells in intestinal tissue from pediatric individuals with Crohn's disease after transient in vitro culture with an ROR-γt inhibitor.

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References

  1. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and TH17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    CAS  PubMed  Google Scholar 

  2. Ivanov, I.I. et al. The orphan nuclear receptor ROR-γt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    CAS  PubMed  Google Scholar 

  3. Gaffen, S.L., Jain, R., Garg, A.V. & Cua, D.J. The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585–600 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Eberl, G. & Littman, D.R. The role of the nuclear hormone receptor ROR-γt in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195, 81–90 (2003).

    CAS  PubMed  Google Scholar 

  5. Sawa, S. et al. ROR-γt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat. Immunol. 12, 320–326 (2011).

    CAS  PubMed  Google Scholar 

  6. Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).

    CAS  PubMed  Google Scholar 

  7. Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A. & Artis, D. CD4+ lymphoid tissue–inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).

    CAS  PubMed  Google Scholar 

  8. Hepworth, M.R. et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria–specific CD4+ T cells. Science 348, 1031–1035 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Hepworth, M.R. et al. Innate lymphoid cells regulate CD4+ T cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mortha, A. et al. Microbiota-dependent cross-talk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    PubMed  PubMed Central  Google Scholar 

  11. Sonnenberg, G.F. & Artis, D. Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat. Med. 21, 698–708 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Papp, K.A. et al. Brodalumab, an anti–interleukin-17 receptor antibody for psoriasis. N. Engl. J. Med. 366, 1181–1189 (2012).

    CAS  PubMed  Google Scholar 

  13. Leonardi, C. et al. Anti–interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).

    CAS  PubMed  Google Scholar 

  14. Genovese, M.C. et al. LY2439821, a humanized anti–interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase 1 randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum. 62, 929–939 (2010).

    CAS  PubMed  Google Scholar 

  15. Hueber, W. et al. Secukinumab, a human anti–IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomized, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Targan, S.R. et al. Mo2083: a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability and efficacy of AMG 827 in subjects with moderate-to-severe Crohn's disease. Gastroenterology 143, e26 (2012).

    CAS  Google Scholar 

  17. Colombel, J.F., Sendid, B., Jouault, T. & Poulain, D. Secukinumab failure in Crohn's disease: the yeast connection? Gut 62, 800–801 (2013).

    CAS  PubMed  Google Scholar 

  18. Gladiator, A., Wangler, N., Trautwein-Weidner, K. & LeibundGut-Landmann, S. Cutting edge: IL-17–secreting innate lymphoid cells are essential for host defense against fungal infection. J. Immunol. 190, 521–525 (2013).

    CAS  PubMed  Google Scholar 

  19. O'Connor, W. Jr. et al. A protective function for interleukin-17A in T cell–mediated intestinal inflammation. Nat. Immunol. 10, 603–609 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kinugasa, T., Sakaguchi, T., Gu, X. & Reinecker, H.C. Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118, 1001–1011 (2000).

    CAS  PubMed  Google Scholar 

  21. Ishigame, H. et al. Differential roles of interleukin-17A and interleukin-17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (2009).

    CAS  PubMed  Google Scholar 

  22. Sonnenberg, G.F., Fouser, L.A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat. Immunol. 12, 383–390 (2011).

    CAS  PubMed  Google Scholar 

  23. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    CAS  PubMed  Google Scholar 

  24. Xiao, S. et al. Small-molecule ROR-γt antagonists inhibit TH17 cell transcriptional network by divergent mechanisms. Immunity 40, 477–489 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Huh, J.R. et al. Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing ROR-γt activity. Nature 472, 486–490 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Solt, L.A. et al. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature 472, 491–494 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Soroosh, P. et al. Oxysterols are agonist ligands of ROR-γt and drive TH17 cell differentiation. Proc. Natl. Acad. Sci. USA 111, 12163–12168 (2014).

    CAS  PubMed  Google Scholar 

  28. Huh, J.R. & Littman, D.R. Small-molecule inhibitors of ROR-γt: targeting TH17 cells and other applications. Eur. J. Immunol. 42, 2232–2237 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Basu, R. et al. TH22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mangan, P.R. et al. Transforming growth factor–β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    CAS  PubMed  Google Scholar 

  31. Klose, C.S. et al. A T-bet gradient controls the fate and function of CCR6−ROR-γt+ innate lymphoid cells. Nature 494, 261–265 (2013).

    CAS  PubMed  Google Scholar 

  32. Vonarbourg, C. et al. Regulated expression of nuclear receptor ROR-γt confers distinct functional fates to NK cell receptor–expressing ROR-γt+ innate lymphocytes. Immunity 33, 736–751 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bernink, J.H. et al. Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues. Nat. Immunol. 14, 221–229 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Song, C. et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869–1882 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Sawa, S. et al. Lineage relationship analysis of ROR-γt+ innate lymphoid cells. Science 330, 665–669 (2010).

    CAS  PubMed  Google Scholar 

  37. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T.R. & Elson, C.O. A dominant, coordinated T regulatory cell–IgA response to the intestinal microbiota. Proc. Natl. Acad. Sci. USA 106, 19256–19261 (2009).

    CAS  PubMed  Google Scholar 

  38. Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

    CAS  PubMed  Google Scholar 

  39. Kaser, A. Not all monoclonals are created equal—lessons from failed drug trials in Crohn's disease. Best Pract. Res. Clin. Gastroenterol. 28, 437–449 (2014).

    CAS  PubMed  Google Scholar 

  40. Aghajani, K., Keerthivasan, S., Yu, Y. & Gounari, F. Generation of CD4CreERT2 transgenic mice to study development of peripheral CD4-T-cells. Genesis 50, 908–913 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Rawlins, E.L., Clark, C.P., Xue, Y. & Hogan, B.L. The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells. Development 136, 3741–3745 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

    CAS  PubMed  Google Scholar 

  43. Bär, E., Whitney, P.G., Moor, K., Reise Sousa, C. & LeibundGut-Landmann, S. IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells. Immunity 40, 117–127 (2014).

    PubMed  Google Scholar 

  44. Feng, T., Wang, L., Schoeb, T.R., Elson, C.O. & Cong, Y. Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis. J. Exp. Med. 207, 1321–1332 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sonnenberg, G.F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mackley, E.C. et al. CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nat. Commun. 6, 5862 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank members of G.F.S.'s and D.R.W.'s laboratories for discussions and critical reading of the manuscript. We also thank C. Elson (University of Alabama at Birmingham) for providing CBir1 transgenic mice and valuable expertise, as well as T. Hohl (Memorial Sloan Kettering Cancer Center) for experimental expertise. Research in the G.F.S.'s laboratory is supported by the National Institutes of Health (DP5OD012116, R56AI114724 and R01AI123368 to G.F.S.), the National Institute of Allergy and Infectious Diseases (NIAID) Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity (to G.F.S.) and the Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the US National Center for Research Resources to G.F.S.) and the Crohn's and Colitis Foundation of America (297365 to M.R.H.). Research in the D.R.W. laboratory is supported by a Wellcome Trust Research Career Development Fellowship (to D.R.W.).

Author information

Author notes

  1. David R Withers and Gregory F Sonnenberg: These authors jointly directed this work.

  2. gfsonnenberg@med.cornell.edu

Authors and Affiliations

  1. MRC Centre for Immune Regulation, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    David R Withers, Emma C Mackley, Emily E Halford, Emma E Dutton & Clare L Marriott

  2. Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, Weill Cornell Medicine, New York, New York, USA

    Matthew R Hepworth, Xinxin Wang & Gregory F Sonnenberg

  3. Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA

    Matthew R Hepworth, Xinxin Wang & Gregory F Sonnenberg

  4. The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, New York, USA

    Matthew R Hepworth, Xinxin Wang & Gregory F Sonnenberg

  5. Babraham Institute, Babraham Research Campus, Cambridge, UK

    Verena Brucklacher-Waldert & Marc Veldhoen

  6. Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Judith Kelsen & Robert N Baldassano

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Contributions

D.R.W. and G.F.S. designed and performed experiments, analyzed data and wrote the paper; M.R.H., X.W., E.C.M., E.E.H., E.E.D., C.L.M., V.B.-W. and M.V. designed and performed experiments; J.K. and R.N.B. provided critical reagents and expertise.

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Correspondence to David R Withers or Gregory F Sonnenberg.

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Withers, D., Hepworth, M., Wang, X. et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells. Nat Med 22, 319–323 (2016). https://doi.org/10.1038/nm.4046

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