Sequential pathogen exposure normalizes the brain neuroimmune microenvironment and reveals a tissue-resident memory CD8 T cell-microglia axis shaping adult neurogenesis

At immune memory timepoints following peripheral pathogen exposures, SPExp mice exhibited CD8 Trm localization near neurogenic niches in the brain. Sholl analysis of microglia in the vicinity of these neurogenic niche CD8s displayed a more activated phenotype. Intravital imaging demonstrated that CD8 Trm are motile and form sustained contacts with microglia in vivo, corresponding to the changes in activation state.

RNAseq identified robust CD8 T cell-dependent transcriptional changes in microglia. Differential expression revealed distinct primed and senescence-associated microglial phenotypes enriched for interferon-signaling, metabolic stress adaptation, and immune surveillance genes and down regulated neuronal support and signaling genes; with reversal of this upon CD8 T cell depletion. Additionally, KEGG/GO analyses suggest induced microglial states downregulate support for neuronal development.

Flow and imaging data found neural stem cells (NSCs) were increased in the niches, but proliferation was abrogated. Proliferation of NSCs was restored after CD8 depletion. Together, these findings identify CD8 Trm as key regulators of microglial state and neurogenesic capacity in the brain, establishing a new paradigm for adaptive immune regulation of brain function at homeostasis.