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The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor best known for mediating the toxicity of dioxin1. Environmental factors are believed to contribute to the increased prevalence of autoimmune diseases, many of which are due to the activity of TH17 T cells, a new helper T-cell subset characterized by the production of the cytokine IL-17. Here we show that in the CD4+ T-cell lineage of mice AHR expression is restricted to the TH17 cell subset and its ligation results in the production of the TH17 cytokine interleukin (IL)-22. AHR is also expressed in human TH17 cells. Activation of AHR by a high-affinity ligand during TH17 cell development markedly increases the proportion of TH17 T cells and their production of cytokines. CD4+ T cells from AHR-deficient mice can develop TH17 cell responses, but when confronted with AHR ligand fail to produce IL-22 and do not show enhanced TH17 cell development. AHR activation during induction of experimental autoimmune encephalomyelitis causes accelerated onset and increased pathology in wild-type mice, but not AHR-deficient mice. AHR ligands may therefore represent co-factors in the development of autoimmune diseases.

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Figure 1: AHR is selectively expressed in the T -H 17 cell subset.
Figure 2: AHR ligation promotes the T H 17 cell programme.
Figure 3: Retroviral transduction of AHR restores IL-22 expression.
Figure 4: EAE is enhanced by AHR ligation.

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Acknowledgements

We thank A. Smith for providing us with the AHR-deficient mouse strain; A. Rae and G. Preece for cell sorting; and Biological Services at NIMR, especially T. Norton and H. Boyes, for animal care and EAE scoring. This work was funded by the Medical Research Council UK.

Author Contributions M.V. and K.H. performed the experiments; A.M.W. and J.B. did the microarrays and analysis; L.D. and J.-C.R. generated and provided the anti-IL-22 antibody; and B.S. directed the research and wrote the manuscript.

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Correspondence to Brigitta Stockinger.

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Veldhoen, M., Hirota, K., Westendorf, A. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008). https://doi.org/10.1038/nature06881

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