Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses

CD8(+) tissue-resident memory T cells (T(RM) cells) are poised at the portals of infection and provide long-term protective immunity. Despite their critical roles, the precise mechanics governing T(RM) cell reactivation in situ are unknown. Using a TCR-transgenic Nur77-GFP reporter to distinguish “antigen-specific” from “bystander” reactivation, we demonstrate that lung CD8(+) T(RM) cells are reactivated more quickly, yet less efficiently, than their counterparts in the draining LNs (T(LN) cells). Global profiling of reactivated memory T cells revealed tissue-defined and temporally regulated recall response programs. Unlike the reactivation of CD8(+) T(LN) cells, which is strictly dependent on CD11c(+)XCR1(+) APCs, numerous antigen-presenting partners, both hematopoietic and non-hematopoietic, were sufficient to reactivate lung CD8(+) T(RM) cells, but the quality of T(RM) cell functional responses depended on the identity of the APCs. Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8(+) memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8(+) T cells.