CD8⁺ T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration

There are changes in adaptive immunity in Alzheimer's disease (AD) and increases in activated CD8⁺ T cells in brain correlate with tau pathology^1-3. However, which cells mediate T cell priming in tau-mediated neurodegeneration remains unclear. In different conditions such as cancer, viral infections, and autoimmune diseases outside the CNS, conventional type-1 dendritic cells (cDC1) perform antigen cross-presentation to prime CD8⁺ T cells^4,5. We demonstrate that tauopathy mice deficient in cDC1 are markedly protected against tau-mediated neurodegeneration and display a selective decrease in brain CD8⁺ T cell infiltration and glial reactivity. The remaining CD8⁺ T cells showed an antigen inexperienced status with less clonal expansion, indicating suboptimal T cell priming. We confirm that brain derived antigens are presented in secondary lymphoid tissues to prime CD8⁺ T cells. Our study identifies cDC1 cells as critical for CD8⁺ T cell priming outside the CNS. This priming is required for a large increase of activated CD8⁺ T cells in the brain which promotes tau-mediated neurodegeneration.