EXPRESSION OF MTB ANTIGENS BY INFECTED MACROPHAGES

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Tuberculosis is the leading cause of death in the world attributable to a single infectious agent. The incidence of tuberculosis is increasing in the United States and strains resistant to conventional antibiotic therapy(s) have emerged. Although vaccination with the BCG strain of Mycobacterium bovis may be beneficial in lowering the incidence of tuberculosis in children, such vaccination provides little, if any, protection for adults. To develop alternate strategies to combat the course of tuberculosis, a better understanding of the mechanisms of pathogenesis and the immune response to Mycobacterium tuberculosis (M. tb.) is required. In particular, identification of the M. tb. derived antigens that are expressed by infected macrophages and elicit T cell responses is required so that new and improved vaccines, designed to upregulate the T cell response to M. tb., can be developed. A number of previous studies have focused on class II restricted responses mediated by CD4+ T cells and the response of CD8+ T cells to M. tb. antigens has been poorly, if at all, characterized. Recent evidence in the mouse model of M. tb. infection suggests that class l restricted responses mediated by CD8+ T cells may be important for protective immunity. The studies described in this proposal will establish whether any of the proteins secreted from M. tb. when grown in culture, contribute to antigenic epitopes in class I molecules on macrophages infected with M. tb. In addition, whether N-formyl-Methionine containing peptides bind to the less polymorphic class lb molecules and elicit reactive T cells will be determined. Evidence that M. tb. peptide epitopes could be presented by class lb molecules from many individuals would provide potentially valuable candidates for M. tb. vaccines. The experimental approach will involve the in vitro restimulation of T cells from both human patients, as well as mice, infected with M. tb. and assayed for class l restricted, M. tb. specific, reactivity. Murine T cell clones with defined specificity for a particular M. tb. protein will be assayed for their ability to confer protective immunity upon adoptive transfer to mice challenged with aerosolized M. tb. The isolation of class I restricted M. tb. reactive T cells will not only identify potential candidates for T cell vaccines, but will also facilitate an analysis of the processing of M. tb. antigens in macrophages from different tissue locations and following exposure to different cytokines.