Identity of recirculating T cells i humans

Abstract Memory T cells are widely considered to continually recirculate between tissues and blood via lymph to maintain immunosurveillance. While much effort has been dedicated to understand which memory T cells that are present in tissues, less is known about peripheral blood memory T cell subsets that recirculate through and egress from tissues during steady-state. Here we directly identify the tissue egressing (recirculating) immune system by sampling thoracic duct lymph (TDL), blood and peripheral tissues in humans and primates. We find that 70% of all immune cells egressing from tissues are T cells. Through transcriptional, functional, clonotypic, and epigenetic profiling, we find that cytolytic memory CD8+ T cell subsets are almost entirely confined to blood, while their phenotypic counterparts in TDL and many tissues represent non-cytolytic cells with higher regenerative capacity. Cytolytic T cells in blood possess a distinct clonotype distribution compared to TDL CCR7- T cells and are retained in blood after treatment with the tissue egress inhibitor fingolimod. We additionally find that HIV-specific CD8+ T cells can be readily found in TDL but again lack a cytolytic phenotype. We propose that cytolytic molecule expression is confined to a blood-resident memory T cell population in steady-state and that the intermediate differentiation status of HIV-specific CD8+ T cells is a fingerprint of their systemic recirculation capacity, rather than dysfunction, in humans.