Developmental plasticity allows outside-in immune responses by resident memory T cells

Central memory T (T_CM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (T_RM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated T_RM cells rejoined the circulating pool. Epigenetic analyses revealed that T_RM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated T_RM cells isolated from small intestine epithelium exhibited the potential to differentiate into T_CM cells, effector memory T cells and T_RM cells on recall. Ex-T_RM cells, former intestinal T_RM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into T_RM cells. Thus, T_RM cells can rejoin the circulation but are advantaged to re-form local T_RM when called on.