Kurzfassung

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. Only few 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 dystrophic neurites surrounding plaques and decreased phosphorylated tau deposition. These effects were accompanied by 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, supporting a previously underappreciated role for CD8⁺ T cells in AD progression.