Hao Hu, Peter Bor-Chian Lin, Carisa Zeng, Yongyi Li, Megan E Bosch, Joshua T Emmerson, Prabal Sharma, Ray A Ohara, Wendy Dong, Tong Wu, Siling Du, Wenqing Gao, Hong Jiang, Liya Yuan, Xin Bao, Shasha Li, Anthony N Vomund, Petra Erdmann-Gilmore, Yichen Gu, Miwei Hu, Jonathan Nulman, Timothy M Miller, Wayne M Yokoyama, Cheryl F Lichti, Jeffrey Milbrandt, Richard J Perrin, Jonathan Kipnis, Maxim N Artyomov, Kenneth M Murphy, Jason D Ulrich, David M Holtzman
Alzheimer's disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity. However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear. In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells. We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation. The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming. We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation. Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration.