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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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.

Author information

Author notes

    • Enric Esplugues
    •  & Samuel Huber

    These authors contributed equally to this work.

Affiliations

  1. Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, 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, California 90048, USA

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

    • Terrence Town
  8. Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, The University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599, 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, Connecticut 06520, 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, Massachusetts 02115, USA

    • Vijay K. Kuchroo
  13. Department of Genetics, LSU Health Sciences Center, New Orleans, Louisiana 70112, USA

    • Jay K. Kolls
  14. Diabetes Center at the University of California San Francisco, San Francisco, California 94143, USA

    • Jeffrey A. Bluestone
  15. Howard Hughes Medical Institute, New Haven, Connecticut 06520, 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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Enric Esplugues or Richard A. Flavell.

Supplementary information

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    Supplementary Figures

    The file contains Supplementary Figures 1-18 with legends.

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    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.

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DOI

https://doi.org/10.1038/nature10228

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