Brain resident memory CD8+ T cells trigger CNS immune activation and infiltration

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Abstract The shifting paradigm regarding immune surveillance of the central nervous system (CNS) has shed light on immune cell networks thought to be absent from healthy brain tissue. Resident memory T cells (TRM) are a unique subset of memory T cells that persist within non-lymphoid tissues to provide rapid onset protection against reinfection. Recently, brain TRM (bTRM) have been identified in humans, with CNS or peripheral infection, or vaccination leading to bTRM establishment in mice. While bTRM are important for protection of the CNS against reinfection, their regulation and involvement in shaping the neuroimmune landscape remains unknown. Here, we take a reductionist approach employing viral-derived peptides to show that CD8+ bTRM reactivation is sufficient to initiate a cascade of innate and adaptive immune activation in the brain. Specifically, bTRM reactivation triggered activation of NK cells, T cells, microglia, and induced dendritic cell (DC) maturation, including upregulation of lymph node homing molecules. Reactivated bTRM also promoted accumulation of DCs in draining lymph nodes, and macrophages, monocyte-derived DCs, T cells and NK cells in the brain. Our preliminary data suggests that PD-1:PD-L1 signaling regulates the magnitude of this response, as PD-L1 blockade led to enhanced bTRM activation and neuroinflammation. We anticipate our results to illuminate roles for PD-1 signaling on bTRM in the context of pathogen clearance, and neurologic toxicities seen in cancer patients following PD-1 inhibitor treatment. This study will also provide insight into the pathologic or protective capacity of bTRM in neurologic diseases where T cells are implicated, such as Alzheimer’s disease, multiple sclerosis, and brain cancer. Supported by grants from NIH (K22 AI148508-02, T32 AI007363)