Abstract
Tissue resident memory T cells (TRM) provide protection against local re-infection, and yet the interstitial signals that govern their formation and persistence remain poorly defined. Here, we show that antigen-dependent induction of the chemokine receptor CXCR6, is a conserved adaptation to peripheral tissue infiltration that promotes TRM formation after viral infection. Deficient TRM formation in the absence of CXCR6 was not explained by trafficking as CXCR6 was not required for tissue entry, was dispensable for the early accumulation of antigen-specific CD8+ T cells in skin, and did not restrain their exit. Single cell sequencing indicated that Cxcr6-/- CD8+ T cells were competent to acquire a transcriptional program of residence and TRM that formed were equally functional compared to their WT counterparts when reactivated greater than 100 days post primary infection. The reduction in Cxcr6-/- CD8+ T cells at memory time points, was associated with impaired redox homeostasis, antioxidant capacity, and increased rates of apoptosis in the dermis during the transition from effector to resident memory. Thus, CXCR6 promotes the adaptation of T cells as they engage antigen in tissue to increase the probability of survival, memory differentiation, and long-term residence.