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Thymic self-reactivity selects natural interleukin 17–producing T cells that can regulate peripheral inflammation

Nature Immunology volume 10, pages 1125–1132 (2009)Cite this article

A Corrigendum to this article was published on 01 January 2010

This article has been updated

Abstract

Interleukin 17 (IL-17)-producing CD4+ helper T cells (TH-17 cells) share a developmental relationship with Foxp3+ regulatory T cells (Treg cells). Here we show that a TH-17 population differentiates in the thymus in a manner influenced by recognition of self antigen and by the cytokines IL-6 and transforming growth factor-β (TGF-β). Like previously described TH-17 cells, the TH-17 cells that developed in the thymus expressed the transcription factor RORγt and the IL-23 receptor. These cells also expressed α4β1 integrins and the chemokine receptor CCR6 and were recruited to the lung, gut and liver. In the liver, these cells secreted IL-22 in response to self antigen and mediated host protection during inflammation. Thus, TH-17 cells, like Treg cells, can be selected by self antigens in the thymus.

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Figure 1: Enrichment for IL-17+ cells in peripheral lymphoid organs of DTg mice.
Figure 2: TH-17 cells develop in the thymus.
Figure 3: Thymic TH-17 development depends on basal production of IL-6 and TGF-β, whereas IFN-γ is inhibitory during peripheral activation.
Figure 4: TH-17 cells from DTg mice express CD44, ICOS but not PD-1.
Figure 5: TH-17 cells from DTg mice express CCR6 and α4β1 integrins and show enrichment in the lamina propria, liver, lung and Peyer's patches.
Figure 6: TH-17 cells from DTg mice produce IL-22 that promotes hepatocyte survival during inflammation.
Figure 7: TH-17 cells in lymph nodes and thymi of wild-type mice have a phenotype identical to that of TH-17 cells in DTg mice.

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  • 05 October 2009

    NOTE: In the version of this article initially published, two relevant papers are not cited. The following brief description of the findings of these papers has been added to the end of the fourth full paragraph on page 1131, and the citations below are now included at the end of the reference list: “Our observations follow the identification in human thymi and umbilical cord blood of CD3+CD4+CD161+ cells that express RORγt, IL-23R and CCR6 and produce IL-17 after activation and stimulation with IL-1 and IL-23 (ref. 54). This work suggested that thymus-derived cells could be precursors of peripheral TH-17 cells in humans, an idea supported by the finding that CD161+IL-17+ cells can be isolated from the intestinal tissue of patients with Crohn's disease55.” 54. Cosmi, L. et al. Human interleukin 17-producing cells originate from a CD161+CD4+ T cell precursor. J. Exp. Med. 205, 1903–1916 (2008). 55. Kleinschek. M.A. et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J. Exp. Med. 206, 525–534 (2009). The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank S. Hedrick (University of California, San Diego) and S. Oehan (University Hospital, Zurich) for AND- and PCC-transgenic mice; F. Alt (The Children's Hospital and Harvard Medical School) and D. Schatz (Yale University School of Medicine) for RAG2:GFP mice; H. van Santen, D. Mathis and C. Benoist (Joslin Diabetes Center and Harvard Medical School) for TA.TIM mice; L. Bockenstedt (Yale University School of Medicine) for CD1d-deficient mice; E. Marks and other members of the Craft laboratory for discussions; L. Zenewicz and E. Espluges for advice; and R. Medzhitov and S. Kaech for critical reading of the manuscript. Supported by the US National Institutes of Heath (AR40072, AR44076, AI56219 and AR053495; and 5T32GM07205 to B.R.M.), the Arthritis Foundation, Rheuminations and the Connecticut chapter of the Lupus Foundation.

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Authors and Affiliations

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

    Benjamin R Marks, Heba N Nowyhed, Jared M Odegard, Richard A Flavell & Joe Craft

  2. Department of Internal Medicine, Section of Rheumatology, Yale School of Medicine, New Haven, Connecticut, USA

    Jin-Young Choi & Joe Craft

  3. Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut, USA

    Amanda C Poholek

  4. Howard Hughes Medical Institute, Yale School of Medicine, New Haven, Connecticut, USA

    Richard A Flavell

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Contributions

B.R.M. and J.C. designed experiments; B.R.M., H.N.N., J.Y. C., A.C.P. and J.M.O. did the experiments; B.R.M., H.N.N., J.Y.C., R.A.F. and J.C. analyzed the data; and B.R.M. and J.C. wrote the paper.

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Correspondence to Joe Craft.

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Marks, B., Nowyhed, H., Choi, JY. et al. Thymic self-reactivity selects natural interleukin 17–producing T cells that can regulate peripheral inflammation. Nat Immunol 10, 1125–1132 (2009). https://doi.org/10.1038/ni.1783

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