Our goal is to investigate the CD4 and CD8 T cell response to pathogenic infectious agents to uncover basic principles of T cell biology in controlling these infections. Two contrasting models of intracellular bacterial pathogens are chosen to ask fundamental questions about how the immune system perceives, responds, contains and eliminates these pathogens. One model to be studied is virulent Mycobacterium tuberculosis delivered via aerosol to the lungs of mice. This organism can survive inside vacuoles within macrophages and set up a chronic infection which can be contained, but not eliminated, by adaptive CD4+T cell immunity. The role of CD8+ T cells in controlling tuberculosis is controversial. Recombinant organisms producing a model antigen containing well-studied epitopes for CD4 and CD8 T cells will allow a study of the tempo of the T cell response, and provide new information on protection against what has been called the world's most successful pathogen..... M. tuberculosis may infect one third of the world's population. The second intracellular pathogen we plan to use is a common food-borne pathogen, Listeria monocytogenes. Excellent mouse models exist already for the study of this Gram positive pathogen, where it appears that adaptive CD8+ T cell immunity is the critical force in eliminating the infection. L. monocytogenes is a candidate vaccine vector for the induction of CD8 immunity, for example, against tumor antigens. The massive response of CD8+ T cells to acute infection with Listeria and the generation of long-lived protective immunity may also require CD4+ T cell help. The proposed studies are aimed at a greater understanding of the development of long-lived, protective immunity induced by this pathogen.
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