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<p>Clonally expanded CD8<sup>+</sup> 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<sup>+</sup> T cells undergo clonal expansion in early-stage AD mouse models, <i>App</i><sup><i>NL-G-F</i></sup> and 5xFAD, and that their depletion reduces amyloid plaque accumulation. Expanded TCR-expressing CD8<sup>+</sup> T cells preferentially infiltrate the brain, exacerbating plaque deposition. Moreover, brain-infiltrating CD8<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells to AD and their potential as therapeutic targets.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月27日

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  • Masaki Ohyagi,
  • Minako Ito,
  • Mana Iizuka-Koga,
  • Setsuko Mise-Omata,
  • Akihiko Yoshimura

摘要

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.