Indiscriminate nature of lung resident CD8+ TRM cells reactivation and their varied reactivation profiles

Abstract CD8+ tissue resident memory (TRM) cells are poised at the portals of infection and confer immediate protection upon reinfection. Despite the critical role of CD8+ TRM cells in long-term protective immunity, the precise mechanics governing their reactivation in-situ are unclear. Seminal work by Leo Lefrançois' group showed that circulating (TCIRC) memory CD8+ T cell depends on CD11c+ antigen-presenting cells (APCs) for reactivation, however, TRM cells are reactivated within peripheral tissues, raising the question of whether the same principle is conserved. We examined this question, focusing on influenza infection, because APCs in the lung are well-defined and lung-resident TRM cells are critical for heterologous immunity to influenza. Using a TCR transgenic Nur77 reporter to delineate TCR-specific from bystander activation in CD8+ TRM cells, we characterized the superior reactivation kinetics in CD8+ TRM cell compared to CD8+ TCIRC. We also identified unique TCR-specific signatures and bystander-specific signatures in the kinetics of CD8+ TRM cells and TCIRC cells reactivation respectively. While we observed the strict requirement for CD11c+APCs in TCR-driven CD8+ TCIRC reactivation, CD8+ TRM cells exhibit promiscuity in their interactions with antigen-presenting partners in that they can be reactivated by both hematopoetic and non-hematopoetic cells. This study explains how the anatomical location of CD8+ TRM cells can confer unique advantage by demonstrating their superior reactivation kinetics and the indiscriminate nature of CD8+ TRM cell reactivation as well as showcasing the transcription profiles of TRM and TCIRC cells following different modes of activation.