CXCR6 promotes dermal CD8⁺T cell survival and transition to long-term tissue residence

Abstract Tissue resident memory T cells (T RM ) provide important protection against infection, and yet the interstitial signals necessary for their formation and persistence remain incompletely understood. Here we show that antigen-dependent induction of the chemokine receptor, CXCR6, is a conserved requirement for T RM formation in peripheral tissue after viral infection. CXCR6 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 also competent to acquire a transcriptional program of residence but exhibited deficiency in multiple pathways that converged on survival and metabolic signals necessary for memory. As such, CXCR6 -/- CD8 + T cells exhibited increased rates of apoptosis relative to controls in the dermis, leading to inefficient T RM formation. CXCR6 expression may therefore represent a common mechanism across peripheral non-lymphoid tissues and inflammatory states that increases the probability of long-term residence. One Sentence Summary CXCR6 promotes mechanisms of cellular adaptation to tissue infiltration that support local survival and the transition to tissue residence.