MHC class I-restricted responses mediated by CD8+ T lymphocytes are not frequently associated with protective immunity to bacterial pathogens. The murine response to Listeria monocytogenes, however, is an exception. Virulent Listeria can access the cytosol of epithelial cells, hepatocytes, macrophages, etc., and the proteins secreted into the host cell cytosol become substrates for MHC class I-restricted processing and presentation. Correlating with this intracellular niche, adoptive transfer and deletion experiments show that CD8+ T-cell immunity is more effective in clearing a Listeria infection than is CD4+ T-cell immunity. Recent work has demonstrated that avirulent forms of Listeria, such as heat-killed organisms, can also present peptide antigen to CD8+ cytotoxic T-cells via the specialized MHC class Ib molecule, H2-M3. H2-M3 can load hydrophobic peptides initiating with fMet derived from Listeria in macrophage phagocytic vacuoles for presentation at the cell surface. Previous work has demonstrated that H2-M3-restricted, CD8+ T-cells can also provide protection against Listeria. The goals of this application are to discover more about the types of bacterial proteins that provide epitopes for M3-restricted immunity. In this way, one may be able to predict which N-terminal peptides of pathogen-derived proteins are presented by this pathway. It is also the goal of the investigator to extend this form of immunity from a single bacterial pathogen which gets into the host cell cytosol, to the broader range of intracellular bacteria that remain enclosed in a host cell vacuole. The investigator aims to shed more light on how MHC class Ia- and class Ib-restricted bacterial antigens are presented to cytotoxic T-cell precursors to initiate a response in vivo.
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