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Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells

Nature Immunology volume 11, pages 846853 (2010) | Download Citation

Abstract

The aryl hydrocarbon receptor (AhR) participates in the differentiation of mouse regulatory T cells (Treg cells) and interleukin 17 (IL-17)-producing helper T cells (TH17 cells), but its role in human T cell differentiation is unknown. We investigated the role of AhR in the differentiation of human induced Treg cells (iTreg cells). We found that AhR activation promoted the differentiation of CD4+Foxp3 T cells, which produce IL-10 and control responder T cells through granzyme B. However, activation of AhR in the presence of transforming growth factor-β1 induced Foxp3+ iTreg cells, which suppress responder T cells through the ectonucleoside triphosphate diphosphohydrolase CD39. The induction of functional Foxp3+ iTreg cells required coordinated action of the transcriptional regulators Smad1 and Aiolos. Thus, AhR is a potential target through which functional iTreg cells could be induced in human autoimmune disorders.

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Acknowledgements

We thank V. Kuchroo (Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School) for discussions and the IL10 promoter reporter construct; Y. Tone and M. Tone (Cedars-Sinai Medical Center) for reporter constructs for FOXP3 +2079 to +2198; and E. Ballestar (Bellvitge Biomedical Research Institute) for vectors encoding Aiolos and its isoforms. Supported by the US National Institutes of Health (AI435801 and NS38037 to H.L.W. and 1K99AI075285 to F.J.Q.), the National Multiple Sclerosis Society (RG4151A12 to H.L.W. and RG4111A1 to F.J.Q.) and the Harvard Medical School Office for Diversity and Community Partnership (to F.J.Q.).

Author information

Author notes

    • Alice Laroni

    Present address: Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Genoa, Italy.

Affiliations

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

    • Roopali Gandhi
    • , Evan J Burns
    • , Meghan Nadeau
    • , Ben Dake
    • , Alice Laroni
    • , Deneen Kozoriz
    • , Howard L Weiner
    •  & Francisco J Quintana
  2. Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA.

    • Deepak Kumar

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Contributions

R.G., D.K., E.J.B., M.N. and A.L. did experiments; D.K. sorted cells by flow cytometry; B.D. provided advice; R.G., D.K., E.J.B., H.L.W. and F.J.Q. analyzed data; R.G. and F.J.Q. wrote the manuscript; and H.L.W. and F.J.Q. supervised the study and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Francisco J Quintana.

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DOI

https://doi.org/10.1038/ni.1915

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