Repeated resident memory T cell reactivation induces sustained microglial activation and decreased Alzheimer’s disease pathology in mice 3913

Abstract Description Resident memory T cells (TRM) are a subset of memory T cells that persist in lymphoid and non-lymphoid tissues. Brain TRM (bTRM) can protect against reinfections, and their reactivation induces transient activation of local immune cells, including microglia. In Alzheimer’s disease (AD), immune involvement has been shown to influence pathology, but the role of TRM in AD progression is largely unknown. Activated microglia can phagocytose amyloid-beta (Aβ) plaques, protein aggregates that are key to AD pathology. Due to increased numbers of CD8+ TRM in AD brains, we sought to test the impact of TRM recall functions on AD pathology. We took a reductionist approach to model recurrent infection by introducing cognate viral peptide intracranially three times one month apart. Consistent with successive expansion, we saw a drastic increase in bTRM numbers in both 5xFAD and wildtype mice. Intriguingly, however, we observed sustained (over one month) microglial activation in only 5xFAD mice by elevated MHCII expression. Females had stronger phenotypes, and strikingly, we observed less insoluble Aβ in female brains but not in males. This amelioration of AD pathology in females was exemplified through increased cognitive plasticity in the reversal phase of the Barnes Maze. This data reveals unique microglial remodeling driven by repeated bTRM reactivation, suggesting a protective role of bTRM in AD and providing insight into neuroimmune crosstalk that can guide AD immunotherapies. Funding Sources Supported by R01AG078761; T32AI007363 Topic Categories Neuroimmunology (NEUR)