Abstract The meningeal and perivascular spaces of the central nervous system (CNS) are inhabited by specialized macrophages, but their homeostatic status and role in orchestrating the immune response against invading pathogens is not well understood. Examination of the naive brain by two-photon microscopy revealed that meningeal and perivascular macrophages are highly dynamic and constantly survey their immediate surroundings similar to microglia. Under steady state conditions, we uncovered that they are maintained in an alternatively activated state, which likely facilitates brain homeostasis. Interestingly, during the development of fatal meningitis induced by lymphocytic choriomeningitis virus, these cells were directly engaged by infiltrating virus-specific CD8+ T cells following acquisition of viral antigen and conversion into an inflammatory phenotype. Mechanistically, microarray analyses revealed that this transition relied on innate cytokine signaling and occurred in the absence of infiltrating inflammatory cells. Using a sub-lethal model of viral meningitis, we observed that despite elimination of previously infected cells, CNS macrophages remained activated for weeks after viral clearance, which was dependent on IFN-g signaling and associated with tissue-resident memory T cell interactions. Collectively, these data indicate that brain-resident macrophages are highly plastic cells that can quickly participate in the antiviral defense against an invading pathogen and can also become imprinted with a prolonged activation program. The inflammatory properties and localization of these cells may explain why most CNS immune responses first develop in the meningeal and perivascular spaces.