Cruz Talavera, I.; Graham, J. B.; Swarts, J. L.; Traxinger, B. R.; Peters, M. Q.; Warrier, L.; Koehne, A. L.; Arkatkar, T.; Jerome, K. R.; Prlic, M.; Lund, J. M.

Many pathogenic human infections enter the host via a mucosal surface. These nonlymphoid tissues are abundantly populated by polyclonal memory CD8 T cells that persist following infections to protect the host in the event of repeat exposure. Memory T cells can be triggered via T cell receptor (TCR) interaction with their cognate antigen upon re-infection to exert effector functions, including cytotoxicity and cytokine production, and assist in pathogen elimination. Alternatively, some T cells are bystander activated by cytokines without antigenic signal. This layered approach boosts efficient pathogen clearance but also poses a threat to host tissues if this response is not properly controlled. Here we investigate the regulatory mechanisms modulating the tissue memory CD8 T cell response upon recall, leveraging mouse models to distinguish antigen-driven versus cytokine-activated memory tissue CD8 T cell immunity. We find that regulatory T cells (Treg) play a role in restricting cytotoxic and bystander activity in mucosal T cells without compromising the antigen-driven protective memory CD8 T cell response. Critically, Treg provide extrinsic regulation of tissue CD8 T cell cytotoxicity through restriction of available IL-2 and IL-15 trans-presentation. Our findings help to define the extrinsic environmental and cellular cues in mucosal tissues that direct tissue memory CD8 T cell cytotoxicity.