CD103–CD8+ T cells promote neurotoxic inflammation in Alzheimer’s disease via granzyme K–PAR-1 signaling
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Immune mechanisms contribute to the neuropathology of Alzheimer’s disease (AD) but the role of adaptive immune cells is unclear. Here we show that the brain CD8+ T cell compartment is dysregulated in AD patients and in a mouse model with the hallmarks of AD, accumulating activated CD103– tissue-resident memory T cells that produce large amounts of granzyme K (GrK). These CD103–CD8+ T cells originate from the circulation and migrate into the brain using LFA-1 integrin. Ablation of brain CD103–CD8+ T cells in AD mice ameliorated cognitive decline and reduced neuropathology. GrK induced neuronal dysfunction and tau hyperphosphorylation in human and mouse cells via protease-activated receptor-1 (PAR-1), which is expressed at higher levels in the AD brain, revealing a novel immune-mediated neurotoxic axis. We conclude that communication between CD8+ T cells and the nervous system is altered in AD, paving the way for therapies targeting T cell-dependent neurotoxic inflammation.