Peripheral dendritic cell priming of CD8+ T cells drives tau-related neurodegeneration

Neurodegenerative tauopathies, such as Alzheimer’s disease, are characterized by the accumulation of hyperphosphorylated, aggregate tau protein and are increasingly recognized as involving adaptive immune responses. Notably, increased infiltration of CD8+ T cells into the brain has been observed in parallel with disease progression, but the mechanisms by which peripheral immune cells contribute to neurodegeneration remain unresolved. In a recent study in Nature Neuroscience, Hao Hu, Peter Bor-Chian Lin, Carisa Zeng and colleagues report that peripheral conventional type 1 dendritic cells (cDC1s) are essential for priming CD8+ T cells, which in turn exacerbate tau-mediated neurodegeneration in a mouse model.

In addition, there was clonal expansion of T cells that was greater in CD8+ T cells than CD4+. Eliminating CD8+ and CD4+ T cells from the periphery of the tau model was neuroprotective. Given this and that previous literature has shown that in the periphery when CD8+ T cells are involved in autoimmune diseases or certain cancers, they need to be first primed cDC1 through a process called cross-presentation.

We thus wanted to test cDC1-dependent CD8+ T cell priming was required for T cell-mediated brain injury in this model of a neurodegenerative disease, which had never been assessed before,” explains David Holtzman, the corresponding author of this study. This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Receive 12 digital issues and online access to articles Prices may be subject to local taxes which are calculated during checkout Nature Aging https://www.nature.com/nataging/ Aman, Y. Peripheral dendritic cell priming of CD8+ T cells drives tau-related neurodegeneration.

Nat Aging (2026). https://doi.org/10.1038/s43587-026-01254-4 DOI: https://doi.org/10.1038/s43587-026-01254-4