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

The aryl hydrocarbon receptor (AHR) is a transcription factor best known for mediating the toxicity of aromatic hydrocarbons such as dioxin: its activation leads to the production of detoxification enzymes. AHR has been intensely studied in relation to toxicology and cancer research, but no mechanistic connection to the immune system was known. Now two groups report a role for AHR in maintaining the balance between two T-lymphocyte populations — the Treg and TH17 cells — that are part of the immune regulation system dealing with tolerance of self-antigens and pathogen clearance. Both groups also show that AHR affects the severity of experimental autoimmune encephalitis, a mouse model of multiple sclerosis. This work raises the possibility that stimulation of AHR by environmental factors could be involved in the development of autoimmune disease, and point to AHR as a possible drug target for immunomodulation. Activation of the aryl hydrocarbon receptor with the ligand FICZ regulates IL-22 expression in TH17 cells. 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.