The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins.
The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor best known for mediating the toxicity of dioxin. Environmental factors are believed to contribute to the increased prevalence of autoimmune diseases, many of which are due to the activity of T(H)17 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 T(H)17 cell subset and its ligation results in the production of the T(H)17 cytokine interleukin (IL)-22. AHR is also expressed in human T(H)17 cells. Activation of AHR by a high-affinity ligand during T(H)17 cell development markedly increases the proportion of T(H)17 T cells and their production of cytokines. CD4+ T cells from AHR-deficient mice can develop T(H)17 cell responses, but when confronted with AHR ligand fail to produce IL-22 and do not show enhanced T(H)17 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.
Veldhoen
Marc
M
Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK.
Hirota
Keiji
K
Westendorf
Astrid M
AM
Buer
Jan
J
Dumoutier
Laure
L
Renauld
Jean-Christophe
JC
Stockinger
Brigitta
B
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000276:immunology* / Q000633:toxicity; D015386:Hazardous Substances / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014161:Transduction, Genetic; D000097043:Interleukin-22
D004785:Environmental Pollutants; D015386:Hazardous Substances; D020381:Interleukin-17; D007378:Interleukins; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D000097043:Interleukin-22