Neurotropic coronavirus-induced encephalitis was used to evaluate recruitment, functional activation, and retention of peripheral bystander memory CD8⁺T cells. Mice were first infected with recombinant vaccinia virus expressing a non-cross-reactive human immunodeficiency virus (HIV) epitope, designated p18. Following establishment of an endogenous p18-specific memory CD8⁺T-cell population, mice were challenged with coronavirus to directly compare recruitment, longevity, and activation characteristics of both primary coronavirus-specific and bystander memory populations trafficking into the central nervous system (CNS). HIV-specific memory CD8⁺T cells were recruited early into the CNS as components of the innate immune response, preceding CD8⁺T cells specific for the dominant coronavirus epitope, designated pN. Although pN-specific T-cell numbers gradually exceeded bystander p18-specific CD8⁺T-cell numbers, both populations peaked concurrently within the CNS. Nevertheless, coronavirus-specific CD8⁺T cells were preferentially retained. By contrast, bystander CD8⁺T-cell numbers declined to background numbers following control of CNS virus replication. Furthermore, in contrast to highly activated pN-specific CD8⁺T cells, bystander p18-specific CD8⁺T cells recruited to the site of inflammation maintained a nonactivated memory phenotype and did not express ex vivo cytolytic activity. Therefore, analysis of host CD8⁺T-cell responses to unrelated infections demonstrates that bystander memory CD8⁺T cells can comprise a significant proportion of CNS inflammatory cells during virus-induced encephalitis. However, transient CNS retention and the absence of activation suggest that memory bystander CD8⁺T cells may not overtly contribute to pathology in the absence of antigen recognition.

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