MR1‐dependent immune surveillance of the skin contributes to pathogenesis and is a photobiological target of UV light therapy in a mouse model of atopic dermatitis

Background Mucosal‐associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I‐related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. Methods Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1‐dependent immune surveillance in a MC903‐driven murine model of AD. Results The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL‐4‐ and IL‐13‐producing cells. In addition, the therapeutic efficacy of phototherapy against MC903‐driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6‐formylpterin. Conclusion We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands. MR1‐restricted presentation of skin‐penetrating bacterial antigens and subsequent MAIT cell activation is a driver of AD. MAIT cell activation is an immunological checkpoint which precedes eosinophil activation. MAIT cell‐deficient MR1 knockout mice are protected from disease. The therapeutic activity of phototherapy (i.e. narrowband UV‐B light therapy) against AD is MR1‐ and folic acid‐dependent. Abbreviations: 5‐OP‐RU, 5‐(2‐oxopropylideneamino)‐6‐D‐ribitylaminouracil; 6‐FP, 6‐formylpterin; AD, atopic dermatitis; APC, antigen‐presenting cell; EOS, eosinophil; MAIT, mucosal‐associated invariant T; MR1, major histocompatibility complex class I‐related molecule; TCR, T cell receptor; UV, ultraviolet light.