CXCR6 orchestrates brain CD8⁺ T cell residency and limits mouse Alzheimer's disease pathology

Neurodegenerative diseases, including Alzheimer's disease (AD), are characterized by innate immune-mediated inflammation, but functional and mechanistic effects of the adaptive immune system remain unclear. Here we identify brain-resident CD8⁺ T cells that coexpress CXCR6 and PD-1 and are in proximity to plaque-associated microglia in human and mouse AD brains. We also establish that CD8⁺ T cells restrict AD pathologies, including β-amyloid deposition and cognitive decline. Ligand-receptor interaction analysis identifies CXCL16-CXCR6 intercellular communication between microglia and CD8⁺ T cells. Further, Cxcr6 deficiency impairs accumulation, tissue residency programming and clonal expansion of brain PD-1⁺CD8⁺ T cells. Ablation of Cxcr6 or CD8⁺ T cells ultimately increases proinflammatory cytokine production from microglia, with CXCR6 orchestrating brain CD8⁺ T cell-microglia colocalization. Collectively, our study reveals protective roles for brain CD8⁺ T cells and CXCR6 in mouse AD pathogenesis and highlights that microenvironment-specific, intercellular communication orchestrates tissue homeostasis and protection from neuroinflammation.