CD103–CD8+ T cells promote neurotoxic inflammation in Alzheimer’s disease via granzyme K–PAR-1 signaling
- Eleonora Terrabuio
- Enrica Caterina 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
2025-09-24
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.