Sympathetic regulation of skin microbiota-induced innate-like T cells

Abstract Recent discoveries in microbiota-mediated neuroimmune crosstalk highlight how co-evolved systems collaboratively facilitate host fitness. However, in the skin – the largest and outermost protective barrier – little is known about the role of microbiota in neuro-immune regulation. We find that murine skin colonization with commensal Staphylococci induces significant accumulation of dermal IL-17A-producing Vg6 +gdT (Vg6 gdT17) cells in IL-1 and microbiota-dependent manner. Compared to sedentary Vg6 gdT17 from unassociated controls, intravital imaging shows that commensal-induced dermal Vg6 gdT17 form large highly motile aggregates. Transcriptomic analysis revealed significant differences between Vg6 gdT17 from commensal-colonized mice versus unassociated controls. Among these, the cells from colonized mice showed significant downregulation of sympathetic beta-adrenoreceptor (bAR) expression. Beta-AR signaling has recently been shown to impact conventional T cell motility in the skin. We observe that, upon systemic b2AR agonist administration, the highly dynamic commensal-induced dermal Vg6 +gdT17 clusters are rendered immobile, showing sympathetic control of gdT17 cell motility. Intriguingly, skin commensal exposure leads to systemic induction of Vg6 +gdT17 cells, implying a role for these cells beyond local surveillance. Further studies are underway to test whether, following exposure to skin commensal, sympathetic regulation promotes inter-organ gdT cell dissemination and impacts their functional potential. Overall, this work aims to uncover the mechanism(s) underlying microbiota-induced skin neuroimmune interactions in promoting organismal homeostasis.