Granzyme K⁺ CD8 T cells slow tauopathy progression by targeting microglia

Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8⁺ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK⁺CD8⁺ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer's disease or chronic traumatic encephalopathy. Deletion of CD8⁺ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK⁺CD8⁺ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression.