Microbially Induced CD8+ Tissue-Resident Memory T Cells Rewire Microglial Function and Suppress Neurogenesis in the Brain 2255642

Abstract

Abstract Introduction T cells are increasingly recognized as long-term residents of the adult brain, displaying regional diversity and accumulating with age; however, functional consequences of T cell residency on brain microenvironment are not well-understood, especially in non-aged populations. Conventionally used young adult Specific Pathogen Free (SPF) mice exhibit low numbers of T cells in the brain compared to young adult humans, limiting translational relevance. In this work we utilize our Specific Pathogen Experienced (SPExp) mouse model, in which prior peripheral infections lead to significant enrichment of tissue-resident memory (Trm) T cells in the brain, generating a neuroimmune state more closely resembling humans. Using this model we recently demonstrated that the presence of T cells in the brain influences seizure outcomes in young mice. Methods Here we combined spectral flow cytometry, single-cell RNA sequencing, and intravital imaging to interrogate the impact of CD8 Trm on brain microenvironment. Results At memory timepoints post peripheral pathogen exposures we identified robust T cell-dependent transcriptional changes in microglia. Differential expression revealed distinct primed and senescence-associated microglial phenotypes enriched for cytokine signaling, antigen presentation and neuroimmune crosstalk; with reversal upon CD8 T cell depletion. Intravital imaging demonstrated that CD8 Trm are motile and form sustained contacts with microglia in vivo, corresponding to the changes in activation state. Additionally, KEGG/GO analyses suggest induced microglial states downregulate support for neuronal development. Consistently, SPExp mice exhibited CD8 Trm localization at neurogenic borders and decreased neural stem cell proliferation, which was restored after CD8 depletion. Conclusion Together, these findings identify CD8 Trm as key regulators of microglial function and neurogenesis, establishing a new paradigm for adaptive immune regulation of brain function at homeostasis. Funding Source Howard Hughes Medical Institute (HHMI) Hanna H. Gray Fellowship Topic Categories Neuroimmunology (NEUR)