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The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27

Nature Immunology volume 11, pages 854–861 (2010)Cite this article

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Abstract

Type 1 regulatory T cells (Tr1 cells ) that produce interleukin 10 (IL-10) are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for the induction of IL-10 by Tr1 cells, but the molecular mechanisms that lead to the development of these cells remain unclear. Here we show that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which was induced by IL-27, acted in synergy with c-Maf to promote the development of Tr1 cells. After T cell activation under Tr1-skewing conditions, the AhR bound to c-Maf and promoted transactivation of the Il10 and Il21 promoters, which resulted in the generation of Tr1 cells and the amelioration of experimental autoimmune encephalomyelitis. Manipulating AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.

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Figure 1: IL-27 upregulates AhR in Tr1 cells.
Figure 2: AhR regulates IL-10 production in Tr1 cells induced by TGF-β and IL-27.
Figure 3: AhR signaling dictates IL-21 secretion in Tr1 cells.
Figure 4: AhR and c-Maf transactivate the Il10 and Il21 promoters in Tr1 cells.
Figure 5: AhR controls the generation of Tr1 cells in vivo.
Figure 6: AhR controls the IL-27-mediated inhibition of EAE.

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Acknowledgements

We thank S.C. Miaw (National Taiwan University College of Medicine) for the IL-21 reporter construct; J. Xu (Mount Sinai School of Medicine) for the IL-10 reporter construct; I-C. Ho (Brigham and Women's Hospital, Harvard Medical School) for Maf-transgenic mice; D. Littman (The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine) for the vector overexpressing AhR-GFP; C. Karp (Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine) for IL-10–enhanced green fluorescent protein reporter mice; and D. Kozoriz for cell sorting. Supported by the US National Institutes of Health (R37NS030843, P01NS038037, P01AI056299 and P01AI039671 to V.K.K.; AI435801 and NS38037 to H.L.W.; 1K99AI075285 to F.J.Q.; and PO1-ES11624 to D.H.S.), the National Multiple Sclerosis Society (RG4111A1 to F.J.Q.), the European Molecular Biology Organization (L.A.), the Harvard Medical School Office for Diversity and Community Partnership (F.J.Q.), the Swiss National Science Foundation (N.J., and SFGBM/PASMA 118720/1 to C.P.) and the Novartis Foundation (C.P.).

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Author notes

  1. Lionel Apetoh, Francisco J Quintana and Caroline Pot: These authors equally contributed to this work.

Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Lionel Apetoh, Francisco J Quintana, Caroline Pot, Nicole Joller, Sheng Xiao, Evan J Burns, Howard L Weiner & Vijay K Kuchroo

  2. Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Deepak Kumar

  3. Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts, USA

    David H Sherr

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Contributions

L.A., F.J.Q. and C.P. did in vitro and in vivo experiments and wrote the manuscript; N.J. did in vivo experiments; S.X., D.K. and E.J.B. did in vitro experiments; D.H.S. provided reagents and advice; and H.L.W. and V.K.K. supervised the study, edited the manuscript and contributed equally to this manuscript.

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Correspondence to Howard L Weiner or Vijay K Kuchroo.

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Apetoh, L., Quintana, F., Pot, C. et al. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11, 854–861 (2010). https://doi.org/10.1038/ni.1912

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