The Impact of a Short-Term Reduction in CD8+ T Cells on Aged APP/PS1 Mice

Abstract CD8⁺ T cells infiltrate the brain parenchyma of patients with Alzheimer’s disease (AD), where they localize near microglia and neurons. Although recent studies have revealed that they can clonally expand and possess a unique phenotype, their contribution to disease pathogenesis remains poorly understood. To investigate the role of these cells in AD, we first performed exploratory immunopeptidome profiling in aged transgenic AD (APP/PS1) mice to identify potential major histocompatibility complex class I-presented antigens that might drive CD8⁺ T cell recruitment. Surprisingly, no peptides were found to be overrepresented in transgenic compared with control brains, suggesting the absence of a dominant antigenic signature. We next characterized brain-infiltrating CD8⁺ T cells by flow cytometry and found that, in aged APP/PS1 mice, these cells exhibit a tissue-resident phenotype distinct from their circulating counterparts. To assess their functional relevance, we induced short-term CD8⁺ T cell depletion in two-year-old APP/PS1 mice using anti-CD8 antibody injections over three days and subsequently analyzed brain pathology and gene expression. CD8⁺ T cell depletion effectively reduced CD8⁺ T cell numbers in both blood and brain. Although amyloid plaque burden remained unchanged, female mice showed reduced LAMP1 + dystrophic neurites surrounding plaques and decreased phosphorylated tau deposition. These effects were accompanied by a modest increase in microglial abundance and elevated hippocampal Il1b expression. Collectively, these findings indicate that brain-resident CD8⁺ T cells contribute to specific aspects of AD-related neurodegeneration in a potential sex-dependent manner (although further experiments are needed), supporting a previously underappreciated role for CD8⁺ T cells in AD progression.