Repeated brain resident memory T cell reactivation induces microglial and T cell remodeling and sustained microglia activation in Alzheimer’s disease

Introduction/Rationale: 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 and recruitment of local immune cells, including microglia. In Alzheimer’s disease (AD), immune involvement has been shown to influence pathology, but the role of bTRM in AD progression is largely unknown. Activated microglia, key mediators of AD pathology, can phagocytose amyloid-beta (Aβ) plaques, protein aggregates that are a hallmark of AD pathology. Due to reported increased numbers of CD8+ TRM in AD brains and the increased risk of AD development through latent viral infections, we sought to test the impact of bTRM recall functions on AD pathology.

Methods: We took a reductionist approach to model TRM reactivation due to recurrent infection by introducing cognate viral peptide intracranially three times one month apart.

Results: Consistent with successive expansion, we saw a dramatic increase in bTRM numbers in both 5xFAD AD-model mice and wildtype mice. Intriguingly, we observed sustained microglial activation as indicated by elevated MHCII expression over one month after the last reactivation in 5xFAD mice. These microglia were part of a cytokine-response microglia subset that were specific to recurrent reactivation in both WT and 5xFAD mice. Additionally, bTRM exhibit increased upregulation of a granzyme-expressing population in response to multiple bTRM recall events. Females had stronger phenotypes, and strikingly, we observed increased soluble Aβ in female brains but not in males.

Conclusion: This data reveals unique microglial and bTRM remodeling driven by repeated bTRM reactivation, suggesting an inflammatory role of bTRM in AD and providing insight into neuroimmune crosstalk that can guide AD immunotherapies.