A critical role and a critical period for herpes simplex virus-specific CD8+ T lymphocyte infiltration into the central nervous system: Impact on the development of stress-induced herpes simplex encephalitis

Despite the generally restrictive nature of the blood-brain barrier, circulating lymphocytes can infiltrate into the central nervous system (CNS) during a variety of disease states.{09}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. A murine model of HSV encephalitis (HSE) has been developed 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, physical restraint. 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. It appears 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. Taken together, these findings identify a critical role for CD8+ T cells in mediating the clinical outcome of HSE and suggest that there exists a critical period of time where CD8+ T lymphocyte infiltration into the brain can be protective against HSE.; To identify the critical period in which CD8+ T cells in the brain can be protective, increasing amounts of CD8+ T cells were adoptively transferred into irradiated mice either one day prior to or three days after HSV-1 infection. Mice receiving the highest levels of CD8+ T cells by adoptive transfer, which were found within the brain following the spread of HSV, were protected against the devastating effects of HSE. In contrast, the adoptive transfer of the same high levels of CD8+ T cells could not confer protection against HSE when administered three days after HSV-I infection. These results clearly demonstrate that not only do CD8+ T cells play a critical role in mediating the outcome of HSE, there also exists a critical period of time whereby the action of CD8+ T cells within the CNS can overcome devastating viral spread and prevent the development of HSE.