CD103–CD8+ T cells promote neurotoxic inflammation in Alzheimer’s disease via granzyme K–PAR-1 signaling
Eleonora Terrabuio, Enrica Pietronigro, Alessandro Bani, Vittorina Della Bianca, Carlo Laudanna, Barbara Rossi, Giulia Finotti, Bruno Santos-Lima, Elena Zenaro, Ermanna Turano, Gabriele Tosadori, Matteo Calgaro, Nicola Vitulo, Monica Castellucci, Daniela Cecconi, Jessica Brandi, Nikolaos Vareltzakis, Fabiana Mainieri, Antonella Calore, Gabriele Angelini, Bruno Bonetti, Gabriela Constantin
Abstract
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 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.