Crosstalk between skin homing innate T cells and epithelial cells via cholesterol byproduct messengers is required for tissue immunity

Abstract

Abstract Innate T cells and innate lymphoid cells (ILCs) in the mucosal tissues are essential for both barrier tissue fitness and immunity against pathogens. γδTCR+ lymphocytes that secrete IL-17 (Tγδ17) localize to dermis and are critical regulators of skin immune responses. Despite their functional importance, how Tγδ17 cells mediate their unique function in the skin is largely unknown. Tγδ17 cells express the two prototypic G-protein coupled receptors (GPCRs) CCR6 and GPR183 (EBI2) that marks most type 3 cytokine (IL-17 and IL-22) producing lymphocytes. Mice lacking both receptors had significantly diminished dermal Tγδ17 cells and were resistant to psoriasis induction. The deficit in dermal Tγδ17 cells in Ccr6−/−Gpr183−/− double knock-out (DKO) mice was attributed to a block in their maturation in the thymus. EBI2 recognizes oxysterols generated by the cholesterol hydroxylase CH25H and functional oxysterols were detected in both the thymus and skin. Analysis of Ch25h-reporter mice showed that a subset of immature medullary thymic epithelial cells (mTEC) is the depot for oxysterols. We confirmed this finding by single cell transcriptome analyses of TECs. These results demonstrate that developing Tγδ17 cells must be conditioned by sensing cholesterol byproducts synthesized by a discrete subset of mTECs. This conditioning is likely to be required to position Tγδ17 cells in specific niches in the skin where oxysterols are generated. Given that CH25H expression can be regulated by infection and inflammation, this sensory circuit directed by cholesterol is predicted to program skin innate T cells’ ability to rapidly survey for perturbations in the skin.