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

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, App^NL-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.