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 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 and Gabriela Constantin ()
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Eleonora Terrabuio: Strada le Grazie 8
Enrica Caterina Pietronigro: Strada le Grazie 8
Alessandro Bani: Strada le Grazie 8
Vittorina Bianca: Strada le Grazie 8
Carlo Laudanna: Strada le Grazie 8
Barbara Rossi: Strada le Grazie 8
Giulia Finotti: University of Verona
Bruno Santos-Lima: Strada le Grazie 8
Elena Zenaro: Strada le Grazie 8
Ermanna Turano: University of Verona
Gabriele Tosadori: Strada le Grazie 8
Matteo Calgaro: Strada Le Grazie 15
Nicola Vitulo: Strada Le Grazie 15
Monica Castellucci: University of Verona
Daniela Cecconi: University of Verona
Jessica Brandi: Strada Le Grazie 15
Nikolaos Vareltzakis: Strada le Grazie 8
Fabiana Mainieri: Strada le Grazie 8
Antonella Calore: Strada le Grazie 8
Gabriele Angelini: Strada le Grazie 8
Bruno Bonetti: P. le Stefani
Gabriela Constantin: Strada le Grazie 8

Nature Communications, 2025, vol. 16, issue 1, 1-24

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.

Date: 2025
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DOI: 10.1038/s41467-025-62405-6

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