Unique phenotypic and T cell receptor characteristics of CD8+ T cells accumulated in the brains of Alzheimer's disease mice.

In Alzheimer’s disease (AD), the involvement of CD8⁺ tissue-resident memory T cells (Trm) have attracted growing interest. During AD pathogenesis, age-associated and AD-associated CD8⁺ T cells may cooperatively influence disease progression; however, their phenotypic and functional differences remain poorly understood. Here, we reanalyzed public single-cell RNA sequencing datasets of brain-derived CD8⁺ T cells from normally aged, wild-type AD, and Cxcr6-deficient AD mice. We identified two major Trm populations: a C-X-C chemokine receptor type 6 (CXCR6)-related immunosuppressive cluster present in aged and wild-type AD mice, and an AD-associated cluster with stem-like features. These clusters were completely phenotypically and clonotypically distinct. Given the proposed role of CXCR6-related CD8⁺ T cells in reducing amyloid-β pathology, their presence in aged mice suggests a protective role. By contrast, the AD-associated cluster exhibited high Tcf7 and Bcl2 expression alongside upregulated immediate-early genes (IEGs), and showed strong clonal overlap with other IEG–enriched clusters. CellChat analysis revealed selective activation of the galectin-9-prolyl 4-hydroxylase pathway in AD-associated Trm-microglia interactions, implicating altered redox regulation. Structural modeling of expanded T cell receptors predicted stable binding to amyloid-β42 peptides, suggesting potential antigen specificity. These findings reveal two transcriptionally and clonotypically distinct CD8+ Trm populations with potentially opposing functions in AD.