Article | Published:

Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor

Nature volume 453, pages 6571 (01 May 2008) | Download Citation

Abstract

Regulatory T cells (Treg) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of Treg cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (TH17). Although Treg cell dysfunction and/or TH17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of Treg and TH17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional Treg cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with Treg cell development, boosted TH17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both Treg and TH17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.

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Acknowledgements

We thank L. I. Zon for helpful discussions and for the critical review of this manuscript; D. Kozoriz and J. P. Schatzmann Peron for help with FACS analysis; and D. Sherr and I. R. Cohen for useful discussions. This work was supported by grants AI435801 and NS38037 from the National Institutes of Health to H.L.W., TA3014A1/1 from the National Multiple Sclerosis Society to E.B. and R01AI073542-01 from the National Institutes of Health and RG-3882-A-1 from the National Multiple Sclerosis Society to M.O. F.J.Q. is a recipient of a long-term fellowship from the Human Frontiers of Science Program Organization; T.K. was supported by the Deutsche Forschungsgemeinschaft (KO 2964/1-1).

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Affiliations

  1. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA

    • Francisco J. Quintana
    • , Alexandre S. Basso
    • , Antonio H. Iglesias
    • , Thomas Korn
    • , Mauricio F. Farez
    • , Estelle Bettelli
    •  & Howard L. Weiner
  2. EMBL Outstation – Hinxton, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK

    • Mario Caccamo
  3. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA

    • Mohamed Oukka

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Correspondence to Howard L. Weiner.

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https://doi.org/10.1038/nature06880

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