CD103–CD8+ T cells promote neurotoxic inflammation in Alzheimer’s disease via granzyme K–PAR-1 signaling

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 the 3xTg-AD mouse model, 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 3xTg-AD mice ameliorates cognitive decline and reduces neuropathology. GrK induces 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 key 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.