Perforin and Fas in murine gammaherpesvirus-specific CD8(+) T cell controland morbidity

The immune system uses both virus-specific T cells and B cells to control t he acute and latent phases of respiratory infection with the murine gammahe rpesvirus 68 (gamma HV-68). We sought to further define the important effec tor mechanisms for CD8(+) T cells. First, depletion of the CD4(+) T cells r esulted in a failure of most animals to drive the virus into latency, altho ugh lytic virus in the lung was reduced by approximately 1000-fold from its peak. Second, the absence of either perforin or Fas alone had no impact on the ability to reduce titres of lytic virus in the lung. Further neutraliz ation of IFN-gamma in CD4-depleted P+/+, P-/- or Fas(-/-) mice had no effec t. To define the requirements for Fas or perforin more clearly, two sets of chimeric mice were constructed differing in perforin expression by the T c ells, and Fas on infected epithelial cells or lymphocytes. Animals with P-/ - T cells and a Fas(-/-) lung failed to limit the shedding of infectious vi rus, regardless of whether CD4 T cells were present. In addition, we noted that having P-/- T cells in irradiated Fas(+/+) hosts caused a lethal disea se that was not apparent in the non-chimeric (unirradiated) P-/- (Fas+/+) m ice. In another set of chimeric mice, P-/- T cells were able to limit persi stent infection of B cells that expressed Fas, but not B cells that were Fa s-deficient. These studies demonstrate that some degree of cytotoxicity via either perforin or Fas is essential for CD8(+) T cells to control this DNA virus.