Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia c
Neurodegenerative diseases trigger innate and adaptive immune responses that can either slow or accelerate disease progression. How immune cells contribute to such divergent disease outcomes is not entirely clear. Here, we sought to define beneficial immune pressure that emerged during development of tauopathies 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 tau throughout the CNS and into the blood. However, over time microglia converted into distressed antigen presenting cells, acquired neuronal transcripts, and were targeted by resident CD8+ T cells. We detected clonally expanded CD8+ T cells in the CNS and draining lymph nodes of tauopathy mice that expressed granzyme K, but not traditional effector molecules (e.g., IFN?, TNF, granzymes a/b/c), which was deposited onto the microglia they targeted. In fact, engagement of microglia by granzyme K expressing CD8+ T cells was a signature of tauopathy development in mice as well as humans with tau rich brain lesions linked to age, Alzheimer's disease, or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the appearance of distressed microglia containing neuronal transcripts, markedly enhanced tau spread, and accelerated neurological decline. These data highlight a beneficial immune reaction involving microglia and granzyme K expressing CD8+ T cells that can slow tauopathy progression. Enhancement of this coordinated response offers the potential to improve outcomes in tauopathy patients. Overall design: 9 bulk RNA-Seq samples representing total RNA isolated from the spinal cords of three different mouse genotypes (WT, P301S heterozygous, and P301S homyzgous).