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, Akihiko Yoshimura
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. Clonally expanded CD8 +T cells drive early Alzheimer’s pathology by suppressing microglial amyloid clearance through CCL5-CCR5 signaling, but later adopt protective roles, thereby revealing a stage-dependent functional transition.