Stage-specific roles of clonally expanded CD8+ T cells in regulating amyloid pathology in Alzheimer’s disease models

Masaki Ohyagi (), Minako Ito, Mana Iizuka-Koga, Setsuko Mise-Omata and Akihiko Yoshimura ()
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Masaki Ohyagi: Tokyo University of Science
Minako Ito: Medical Institute of Bioregulation Kyushu University
Mana Iizuka-Koga: Tokyo University of Science
Setsuko Mise-Omata: Tokyo University of Science
Akihiko Yoshimura: Tokyo University of Science

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Clonally expanded CD8+ T cells may contribute to Alzheimer’s disease (AD) pathology through interactions with brain-resident cells. However, the functional impact of AD-specific T cell receptor (TCR) clonotypes remains unclear. Here, we demonstrate that CD8+ T cells undergo clonal expansion in early-stage AD mouse models, AppNL-G-F and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8+ T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8+ T cells impair microglial transition into disease-associated states, suppressing amyloid clearance via CCL5-CCR5 signaling. Pharmacological blockade of CCL5 attenuates amyloid deposition, whereas CCL5 administration aggravates pathology. Notably, T cell depletion at later disease stages exacerbates amyloid pathology, suggesting a temporal shift in their function. Early-stage CD8+ T cells exhibit cytotoxic and effector profiles, whereas late-stage cells acquire tissue-resident and exhausted phenotypes. This temporal switch—from pathogenic to protective roles—highlights the stage-specific contribution of CD8+ T cells to AD and their potential as therapeutic targets.

Date: 2025
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DOI: 10.1038/s41467-025-64503-x

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