MAIT cells support Treg response to UV light in healthy skin and restrain CD8 activation in lupus skin 2257500

Abstract

Abstract Introduction MAIT cells are innate-like T cells enriched in barrier sites, including the skin, that exhibit both repair and inflammatory functions. UV light induces immunosuppression in healthy but not lupus (SLE) skin. We tested whether MAIT cells enable this regulatory program and how it fails in SLE. Methods B6, MAIT-deficient (Mr1-/-), and SLE (MRL/lpr or TLR7 agonist) mice (8 wks, F) were exposed to chronic UVB (50mJ/cm2 daily, x 2 or 6). Contact hypersensitivity (CHS) was induced by skin sensitization, then challenged with hapten, DNFB, 6 days later. MAITs were expanded by topical antigen, 5OPRU (1mM, every 48hr x 4). MAITs (5OPRU-loaded MR1 tetramer) and Treg were assessed by flow cytometry. Results UV exposure led to ∼5-fold expansion of MAITs and Treg in B6 skin. MAITs were required for Treg expansion; no change in Treg was seen after UV in Mr1-/- skin. Early after UV (x 2), Treg in Mr1-/- skin exhibited a fragile phenotype (NRP1loGITRloICOSloPD1hiCD69hi). After chronic UV (x 6), B6 but not Mr1-/- skin Treg upregulated immunosuppressive (ICOS, CTLA4, CD120b) and repair (ST2) proteins. UV before sensitization with DNFB prevented CHS upon challenge in B6 but not Mr1-/- skin, revealing loss of immunosuppression in the absence of MAITs. Like Mr1-/- skin, Treg did not proliferate or expand after UV in MRL/lpr skin. Instead, CD8 T cells increased ∼10-20-fold, causing a marked reduction in the Treg:CD8 ratio. Similar reduction in Treg:CD8 ratio was seen after UV in the TLR7 SLE model in Mr1-/- but not B6 skin. Topical expansion of MAITs with 5OPRU before UV restored the Treg:CD8 ratio, and CD8s in MAIT-expanded skin expressed less Ki67, CD69, PD1, and CXCR6. Conclusion In healthy skin, MAITs are required for UV-induced Treg expansion. This mechanism fails in SLE-like skin, allowing unchecked expansion and activation of CD8 T cells. Topical expansion of MAITs restores the skin immunosuppressive response to UV, revealing a novel avenue for therapeutic intervention in skin inflammatory disease. Funding Source NIAMS R01AR080641 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)