Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia 3928

Abstract Description Neurodegenerative diseases trigger innate and adaptive immune responses that can either slow or accelerate disease progression. 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. Single cell TCR sequencing revealed 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., IFNg, TNF, granzymes a/b/c), which was deposited onto the microglia they targeted. 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. Funding Sources This work was supported by the intramural program at the National Institute of Neurological Disorders & Stroke and the National Institute of Allergy & Infectious Diseases, NIH, as well as The Defense Health Agency (310286-1.00-65642 and 311661-5.00-66323). Topic Categories Neuroimmunology (NEUR)