Abstract
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.
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Abstract
There are changes in adaptive immunity in Alzheimer’s disease (AD) and increases in activated CD8+ T cells in brain correlate with tau pathology1–3. 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 cells4,5. 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.
Competing Interest Statement
D.M.H. co-founded, has equity, and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Genentech, Denali, and Cajal Neuroscience and consults for Pfizer, Asteroid, Switch Therapeutics, and Roche. All other authors declare no competing interests.
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