Regulatory T cells restrain cytotoxic and bystander CD8 T cells without compromising antigen-driven memory in mucosal tissue

ABSTRACT/SUMMARYMany 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 for protection upon repeat exposure. Memory T cells can be triggered via T cell receptor recognition of 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 an antigenic signal. This layered approach boosts efacient 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 viral rechallenge mouse models to distinguish antigen-driven versus cytokine-activated memory tissue CD8 T cell immunity. We and that regulatory T cells (Treg) participate in restricting cytotoxic and bystander activity without compromising the antigen-driven protective memory CD8 T cell response in mucosal T cells. Critically, Treg provide extrinsic regulation of tissue CD8 T cell cytotoxicity in part through restriction of available IL-2 and IL-15 trans-presentation. Our andings help deane the extrinsic environmental and cellular cues in mucosal tissues that direct tissue-memory CD8 T cells.