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Control of TH17 cells occurs in the small intestine

Nature volume 475, pages 514–518 (2011)Cite this article

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Abstract

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells1. TH17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE)2, the mouse model for multiple sclerosis. The factors that are needed for the generation of TH17 cells have been well characterized3,4,5,6. However, where and how the immune system controls TH17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine. TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory TH17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17). These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells.

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Figure 1: Accumulation of T H 17 cells in the small intestine after CD3-specific antibody treatment.
Figure 2: The axis CCR6/CCL20 is essential for the recruitment of T H 17 cells to the small intestine.
Figure 3: Functional and molecular characterization of rT H 17 cells.
Figure 4: T H 17 cells are recruited to the small intestine during sepsis.

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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)

    Article  CAS  Google Scholar 

  2. Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005)

    Article  CAS  Google Scholar 

  3. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  5. Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nature Immunol. 9, 641–649 (2008)

    Article  CAS  Google Scholar 

  6. Yang, L. et al. IL-21 and TGF-β are required for differentiation of human TH17 cells. Nature 454, 350–352 (2008)

    Article  ADS  CAS  Google Scholar 

  7. Hirota, K. et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007)

    Article  CAS  Google Scholar 

  8. Merger, M. et al. Defining the roles of perforin, Fas/FasL, and tumour necrosis factor α in T cell induced mucosal damage in the mouse intestine. Gut 51, 155–163 (2002)

    Article  CAS  Google Scholar 

  9. Chatenoud, L. & Bluestone, J. A. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nature Rev. Immunol. 7, 622–632 (2007)

    Article  CAS  Google Scholar 

  10. Herold, K. C. et al. Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years. Clin. Immunol. 132, 166–173 (2009)

    Article  CAS  Google Scholar 

  11. Carpenter, P. A. et al. Non-Fc receptor-binding humanized anti-CD3 antibodies induce apoptosis of activated human T cells. J. Immunol. 165, 6205–6213 (2000)

    Article  CAS  Google Scholar 

  12. Smith, C. A., Williams, G. T., Kingston, R., Jenkinson, E. J. & Owen, J. J. Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures. Nature 337, 181–184 (1989)

    Article  ADS  CAS  Google Scholar 

  13. Perruche, S. et al. CD3-specific antibody-induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells. Nature Med. 14, 528–535 (2008)

    Article  CAS  Google Scholar 

  14. Chatenoud, L., Primo, J. & Bach, J. F. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J. Immunol. 158, 2947–2954 (1997)

    CAS  PubMed  Google Scholar 

  15. Alegre, M. L. et al. An anti-murine CD3 monoclonal antibody with a low affinity for Fc gamma receptors suppresses transplantation responses while minimizing acute toxicity and immunogenicity. J. Immunol. 155, 1544–1555 (1995)

    CAS  PubMed  Google Scholar 

  16. Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003)

    Article  CAS  Google Scholar 

  17. Annunziato, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007)

    Article  CAS  Google Scholar 

  18. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514–523 (2009)

    Article  CAS  Google Scholar 

  19. Brown, S. J. & Mayer, L. The immune response in inflammatory bowel disease. Am. J. Gastroenterol. 102, 2058–2069 (2007)

    Article  ADS  CAS  Google Scholar 

  20. Petitto, J. M., Streit, W. J., Huang, Z., Butfiloski, E. & Schiffenbauer, J. Interleukin-2 gene deletion produces a robust reduction in susceptibility to experimental autoimmune encephalomyelitis in C57BL/6 mice. Neurosci. Lett. 285, 66–70 (2000)

    Article  CAS  Google Scholar 

  21. Pestka, S. et al. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929–979 (2004)

    Article  CAS  Google Scholar 

  22. McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nature Immunol. 8, 1390–1397 (2007)

    Article  CAS  Google Scholar 

  23. Kohm, A. P. et al. Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. J. Immunol. 174, 4525–4534 (2005)

    Article  CAS  Google Scholar 

  24. Khader, S. A., Gaffen, S. L. & Kolls, J. K. Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol. 2, 403–411 (2009)

    Article  CAS  Google Scholar 

  25. Rodriguez-Creixems, M. et al. Bloodstream infections: evolution and trends in the microbiology workload, incidence, and etiology, 1985–2006. Medicine (Baltimore) 87, 234–249 (2008)

    Article  Google Scholar 

  26. Martin, G. S., Mannino, D. M., Eaton, S. & Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med. 348, 1546–1554 (2003)

    Article  Google Scholar 

  27. Ochi, A., Yuh, K. & Migita, K. Not every superantigen induces tolerance in vivo . Semin. Immunol. 5, 57–63 (1993)

    Article  CAS  Google Scholar 

  28. Soos, J. M., Schiffenbauer, J. & Johnson, H. M. Treatment of PL/J mice with the superantigen, staphylococcal enterotoxin B, prevents development of experimental allergic encephalomyelitis. J. Neuroimmunol. 43, 39–43 (1993)

    Article  CAS  Google Scholar 

  29. Chowell, G. et al. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N. Engl. J. Med. 361, 674–679 (2009)

    Article  CAS  Google Scholar 

  30. Bettelli, E. et al. Myelin oligodendrocyte glycoprotein-specific T cell receptor transgenic mice develop spontaneous autoimmune optic neuritis. J. Exp. Med. 197, 1073–1081 (2003)

    Article  CAS  Google Scholar 

  31. Wan, Y. Y. & Flavell, R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl Acad. Sci. USA 102, 5126–5131 (2005)

    Article  ADS  CAS  Google Scholar 

  32. Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002)

    Article  CAS  Google Scholar 

  33. Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–528 (2001)

    Article  CAS  Google Scholar 

  34. Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952 (2006)

    Article  CAS  Google Scholar 

  35. Alegre, M. L. et al. An anti-murine CD3 monoclonal antibody with a low affinity for Fc gamma receptors suppresses transplantation responses while minimizing acute toxicity and immunogenicity. J. Immunol. 155, 1544–1555 (1995)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank F. Manzo for expert administrative assistance, L. Evangelisti and C. Hughes for generating embryonic stem cells and chimaeric mice, respectively, J. Stein for initial screening of knock-in mice, T. Ferrandino for assistance with the mouse colony, E. Eynon and J. Alderman for managing the mouse program and A. Lin for assistance with Gene Array analysis. We also thank T. Taylor and G. Tokmoulina for expert help with the FACS sorting and D. Gonzalez for help with the multiphoton microscopy. We would like to thank J. P. Allison for providing the anti-CTLA-4 antibody, F. Waldron-Lynch and J. S. Pober for providing peripheral blood mononuclear cells, and the NIH Tetramer core facility for providing the tetramers. W.O. was supported by a fellowship from the National Multiple Sclerosis Society. S.H. was supported by the DFG (HU 1714/1-1) and by a James Hudson Brown–Alexander B. Coxe Fellowship. E.E. was supported by the Spanish Ministry of Science postdoctoral fellowship and by a James Hudson Brown–Alexander B. Coxe Fellowship. R.A.F. is an Investigator of the Howard Hughes Medical Institute. The generation of mice for this work was supported by the Transgenic Core of the Yale DERC DK45735 and some of the work supported by a Pilot project from DK45735. This work was also supported by the JDRF.

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Author notes

  1. Enric Esplugues and Samuel Huber: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Enric Esplugues, Samuel Huber, William O’Connor, Anthony Rongvaux, Kevan C. Herold & Richard A. Flavell

  2. German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin 10117, Germany

    Enric Esplugues & Anja E. Hauser

  3. Cluster of Excellence NeuroCure, Charite-Universitätsmedizin Berlin, Berlin 10117, Germany

    Enric Esplugues

  4. I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20246, Germany

    Samuel Huber

  5. San Raffaele Diabetes Research Institute (HSR-DRI), Milan 20132, Italy

    Nicola Gagliani

  6. Departments of Biomedical Sciences and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, 90048, California, USA

    Terrence Town

  7. Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, 90048, California, USA

    Terrence Town

  8. Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina, School of Medicine, Chapel Hill, 27599, North Carolina, USA

    Yisong Y. Wan

  9. Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit, Amsterdam, 1081 BT, The Netherlands

    Nico Van Rooijen

  10. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Ann M. Haberman

  11. Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

    Yoichiro Iwakura

  12. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Vijay K. Kuchroo

  13. Department of Genetics, LSU Health Sciences Center, New Orleans, 70112, Louisiana, USA

    Jay K. Kolls

  14. Diabetes Center at the University of California San Francisco, San Francisco, 94143, California, USA

    Jeffrey A. Bluestone

  15. Howard Hughes Medical Institute, New Haven, 06520, Connecticut, USA

    Richard A. Flavell

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Contributions

E.E., S.H. and R.A.F. designed the study and wrote the manuscript; N.G. did the in vitro suppression assays and the flow analysis for IL-10 expression; A.E.H. and A.M.H did the two-photon laser-scanning microscopy experiments; T.T. did the immunohistochemistry analysis; W.O. supported the work with key suggestions and by editing the manuscript; E.E. and S.H. did all other in vitro and in vivo experimental work; Y.Y.W. provided Foxp3–mRFP mice; A.R. did the viral infection experiments; N.V.R. provided clodronate-loaded liposomes, V.K.K provided 2D2 mice and feedback on the manuscript; Y.I. provided Il17a–/– mice and feedback on the manuscript; J.K.K. provided the Il17ra–/– mice and feedback on the manuscript and J.A.B. provided CD3-specific antibodies and feedback on the manuscript; K.C.H. provided teplizumab and key suggestions. E.E. and R.A.F. co-directed the project.

Corresponding authors

Correspondence to Enric Esplugues or Richard A. Flavell.

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The authors declare no competing financial interests.

Supplementary information

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The file contains Supplementary Figures 1-18 with legends. (PDF 2421 kb)

Supplementary Movie 1

The movie shows Multiphoton analysis of the small intestine of IL17A–eGFP x FoxP3–mRFP double reporter mice during CD3-specific antibody treatment. (MOV 6677 kb)

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Esplugues, E., Huber, S., Gagliani, N. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011). https://doi.org/10.1038/nature10228

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