CD8+ T cells are important mediators of immunity against many viral, protozoan and bacterial pathogens of humans. Activated CD8+ T cells respond to pathogen infected cells by elaborating several distinct effector mechanisms, including cytolysis, IFN-gamma and TNF-alpha production, with the potential to resist infection. In order to design successful vaccines against infectious agents it critical to understand which effector mechanisms and cells provide the most potent immunity. Given the complex biology of intracellular pathogens and the variety of strategies they use to avoid host immune responses it is unlikely that identical CD8+ T cell effector mechanisms will be required for resistance to all types of intracellular pathogens. Substantial research effort has been made to understand the CD8+ T cell effector mechanisms that provide immunity to viral infections. However, similar studies of CD8+ T cell effector mechanisms in resistance to protozoan and bacterial pathogens are lacking. The long term objectives of this research are to understand the CD8+ T cell effector mechanisms that provide immunity against intracellular bacteria. Studies in this proposal will use a well characterized mouse model of infection with the human enteric pathogen Listeria monocytogenes to test the hypothesis that at least one of the major CD8+ T cell effector mechanisms (cytolysis, IFN-gamma or TNF-alpha production) is required for CD8+ T cell mediated immunity to L. monocytogenes infection. The following specific aims will be addressed.
Specific Aim -1. Determine the requirement for perforin dependent cytolysis in CD8+ T mediated immunity against L. monocytogenes infection.
Specific Aim -2. Determine the requirement for CD8+ T cell derived IFN-gamma in immunity to L. monocytogenes infection in the absence of perforin.
Specific Aim -3. Determine the requirement for TNF- alpha in: a) secondary resistance to L. monocytogenes infection and b) as a CD8+ T cell effector mechanism in the presence and absence of perforin and INF-gamma. Our experimental approach to these aims combines genetically manipulated L. monocytogenes strains, specific gene knockout mice, antigen specific CD8+ T cells and neutralizing anti- cytokine antibodies. These reagents provide sophisticated probes for identification of the CD8+ T cell effector mechanisms required for immunity to intracellular bacteria. The results of these studies will provide important information for vaccine design strategies and emerging approaches to the immunotherapy of human infectious diseases.
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