title: 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.
authors.affiliation: Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
authors.forename: Crystal S
authors.initials: CS
authors.lastname: Anglen
authors.forename: M E
authors.initials: ME
authors.lastname: Truckenmiller
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bonneau
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002465:Cell Movement / Q000276:immunology; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D020803:Encephalitis, Herpes Simplex / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000276:immunology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological / Q000276:immunology*; D014614:Vaccines, Synthetic / Q000008:administration & dosage; D014616:Vaccinia virus / Q000276:immunology; D014709:Vero Cells; D014765:Viral Vaccines / Q000008:administration & dosage
chemical_list: D018984:Epitopes, T-Lymphocyte; D014614:Vaccines, Synthetic; D014765:Viral Vaccines