UV irradiation-mediated systemic immune suppression through AHR signalling

      Risk and disease activity in multiple sclerosis (MS) are modulated by multiple environmental factors, including smoking and exposure to UV light. Epidemiological studies have demonstrated that the incidence and severity of MS are inversely correlated with sunlight exposure. Although clinical trials using vitamin D as a therapy for MS are underway, recent evidence from studies in experimental autoimmune encephalomyelitis (EAE) has raised doubt for the UV-mediated production of vitamin D as the sole responsible factor for the protective effect of UV light. The amino acid l-tryptophan (Trp) serves not only as a building block for proteins and neurotransmitters, but is also involved in the regulation of immune responses. Several Trp metabolites have been demonstrated to bind, activate and mediate immune-modulation via the aryl hydrocarbon receptor (AhR). A key and high affinity ligand, 6-formylindolo[3,2-b]carbazole (FICZ), is a photoproduct of tryptophan, generated by UV light and implicated in the differentiation of CD4+ T cells and dendritic cells. Therefore we tested the hypothesis that UV irradiation of the skin suppresses antigen-specific immune responses via the AhR in experimental autoimmune encephalomyelitis (EAE). Reporter mice were generated to monitor AhR activation in vivo (DRELuc). Exposure of DRELuc mice to UV light induced a rapid activation of the AhR in the skin paralleled by an activation of AhR target genes, chiefly cytochrome P 450 oxidase 1A1, selective depletion of skin dendritic cells, particularly Langerhans cells, and accumulation of specific UV-regulatory T cells in the draining lymph nodes. Strikingly, exposure to UV light resulted in a delayed onset of EAE in wildtype but not AhR-deficient mice. Our data suggest that UV irradiation suppresses systemic antigen-specific T cell responses via the AhR.
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