CXCR6 is required for tissue resident memory T cell formation across diverse peripheral non-Lymphoid tissues

Abstract CD8 T cell control of viral infections in peripheral tissues is largely dependent upon their spatial positioning. Clearance of pathogens requires direct contact between CD8 T cells and infected cells. Chemokine receptors play an essential role in this process by facilitating T cell entry into tissues, directing T cell positioning within tissues and by influencing egress out of tissues. Tissue resident memory T cells (TRM), which fail to egress after pathogen clearance and scan cells for signs of infection, are potent sources of immunity to secondary encounters with pathogens. Here we show that expression of the chemokine receptor CXCR6 is a conserved feature of TRM after viral infection in many non-lymphoid tissues. Using CXCR6KO TCR-tg T cells, we found that CXCR6 is necessary for proper formation of TRM in all non-lymphoid tissues examined. CXCR6 was necessary for early accumulation of effector T cells in several tissues such as the kidney and salivary gland but CXCR6 was dispensable for early accumulation in the skin. After vaccinia infection in the skin, CXCR6 expression is reinforced upon antigen re-encounter and promotes CD8 T cell accumulation in a migration-independent manner. Using single cell transcriptional analysis, we show that CXCR6KO TRM appear to exhibit a survival disadvantage and are outcompeted by wildtype T cells. This work reveals a critical requirement for generating TRM in diverse anatomical locations and may benefit strategies for vaccine design, anti-tumor immunity and reducing T-cell mediated autoimmunity. Supported by R01CA238163 T32Al100853-10