Mycobacterium avium is the most common cause of disseminated bacterial infection in AIDS patients. M. avium primarily infect macrophages, where they are thought to survive and multiply in membrane-bound vesicles that resist fusion with lysosomes. As with most intracellular pathogens, cell-mediated immunity is required for protection against M. avium infection. However, little is known about the specific roles of the various T cell subsets in clearing mycobacterial infections. We have been able to culture CD8+ cytotoxic T lymphocytes (CTL) from the spleens of mice infected with M. avium. This observation suggests that there are mycobacterial protein antigens that can access the host cell cytoplasm for processing and presentation on the cell surface by class I MHC molecules. The experiments outlined in this proposal are designed to test the overall hypothesis that CTL are generated against several different M. avium protein antigens, and that these CTL are important for inhibiting proliferation of M. avium during the later stages of infection. Our approach will be to generate various M. avium-specific CTL lines and to characterize their peptide epitope specificity and their ability to clear M. avium infections upon adoptive transfer into mice. In addition, we will determine if there is a requirement for protein antigen secretion in order to generate an M. avium-specific CTL response. These studies will lead to a greater understanding of both the host response to mycobacterial infections and the processing and presentation of protein antigens produced by intracellular pathogens.
| D'Orazio, S E; Halme, D G; Ploegh, H L et al. (2003) Class Ia MHC-deficient BALB/c mice generate CD8+ T cell-mediated protective immunity against Listeria monocytogenes infection. J Immunol 171:291-8 |
