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_RM) CD8⁺ T cells. However, the impact of repeated peripheral viral infection on the generation, phenotype, localization, and recall responses of brain T_RM 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_RM compared to naive CD8⁺ T cells. Repetitively stimulated brain T_RM also demonstrate differential inhibitory receptor expression, preserved functionality, and divergent localization patterns compared to primary memory counterparts. Despite these differences, repetitively stimulated brain T_RM 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_RM pool that is dictated by prior peripheral antigen stimulation history.