Repetitive antigen stimulation in the periphery dictates the composition and recall responses of brain-resident memory CD8 T cells.

The human brain harbors virus-specific, tissue-resident memory (T) CD8 T cells. However, the impact of repeated peripheral viral infection on the generation, phenotype, localization, and recall responses of brain T remains elusive. Here, utilizing two murine models of peripheral viral infection, we demonstrate that circulating memory CD8 T cells with previous antigen exposure exhibit a markedly reduced capacity to form brain T compared to naive CD8 T cells. Repetitively stimulated brain T also demonstrate differential inhibitory receptor expression, preserved functionality, and divergent localization patterns compared to primary memory counterparts. Despite these differences, repetitively stimulated brain T provide similar protection against intracranial infection as primary populations with superior recall-based recruitment of peripheral lymphocytes. As CD8 T cells may distinctly seed the brain with each repeated infection of the same host, these findings point to heterogeneity in the brain T pool that is dictated by prior peripheral antigen stimulation history.