The dual role of CD8+ T lymphocytes in the development of stress-induced herpes simplex encephalitis

Abstract

Despite the generally restrictive nature of the blood-brain barrier (BBB), circulating lymphocytes can infiltrate into the central nervous system (CNS) during a variety of disease states. Although the contributions of these lymphocytes to CNS-associated disease have been identified in some viral models, the factors which govern this infiltration following herpes simplex virus (HSV) infection remain to be elucidated. We have developed a murine model of HSV encephalitis (HSE) to define the relationship among psychological stress, the recruitment of HSV-specific T cells into the CNS, and the development of HSE. Naive mice, as well as mice that had been vaccinated with a recombinant vaccinia virus (rVVESgB498-505) that elicits the generation of HSV-1 gB498-505-specific CD8(+) T cells, were infected intranasally (i.n.) with HSV-1 McIntyre. Beginning one day prior to HSV-1 infection and continuing for a total of 9 days, naive and vaccinated mice were exposed to a well-established stressor, restraint stress. Naive, stressed mice exhibited increased symptoms of HSE and HSE-associated mortality as compared to non-stressed controls. A concomitant increase in CD4(+) and CD8(+) T cells in the brain was observed throughout the infection, with CD8(+) T cells outnumbering CD4(+) T cells. The development of HSE in these naive, stressed mice was accompanied by a delayed infiltration of gB498-505-specific CD8(+) T cells after HSV spread into the brain. In contrast, both stressed and non-stressed rVVESgB498-505-vaccinated mice possessed gB498-505-specific CD8(+) T cells prior to HSV challenge and were protected against HSE despite having detectable HSV-1 DNA in the brain. Together, these findings suggest that a delayed infiltration of CD8(+) T cells into the brain may promote HSE in naive mice, while the presence of HSV-specific CD8(+) T cells in the brain prior to HSV challenge is protective, possibly by limiting HSV replication and spread within the CNS.