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 in barrier tissues are essential for both 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): mice lacking both receptors had significantly diminished dermal Tγδ17 cells and were resistant to psoriasis induction. This was due to a block in Tγδ17 cell maturation in the thymus of Ccr6−/−Gpr183−/− double knock-out mice. 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 interfollicular epithelial cells (IFEs) and a subset of medullary thymic epithelial cells (mTEC) are the depot for oxysterols in skin and thymus respectively. Ch25h+ TECs were also identified by unbiased single cell transcriptome analyses. These results demonstrate that developing Tγδ17 cells must be conditioned by sensing cholesterol byproducts synthesized by a discrete subset of mTECs to position in specific oxysterol rich niches in the skin. Moreover, in the skin, dietary cholesterol increased tissue oxysterol concentration and modulated homeostatic and pathogenic effector function of Tγδ17 cells in a EBI2 dependent fashion. Given that oxysterols 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. Supported by grant from NIH R21AI143225.