Inhibition of T cell Responses by Bacteria

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EXCEED THE SPACE PROVIDED. We have initiated studies to characterize the role of CD8 + T cells in immunity to the intracellular bacterium, Shigellaflexneri. During infection, S. flexneri enters cells and escapes into the host cell cytosol. We expected that proteins excreted from Shigella would be proteolytically degraded into peptides by the MHC-I processing pathway, and that the resulting cell-surface peptide:MHC-I complexes would stimulate CD8 + T-cells. During infection with Listeria monocytogenes, another cytosolic bacterial pathogen, Listeria- derived peptides, in complex with host MHC-I, are recognized by CD8 ¿ T cells and contribute to the generation of protective immunity. However, we have found that CD8 + T cells do not appear to play a role in protective immunity to S. flexneri. Even when the Shigella have been engineered to constitutively secrete heterologous epitopes known to stimulate potent CD8 + T cell responses, those responses were not dectected. We also found that when cultured cells were infected with these epitope-tagged S. flexneri strains, the cells were not recognized by established T-cell clones specific for the epitope tag. These findings have suggested to us that a step (or steps) in the normal MHC-I processing pathway is inhibited in cells infected with S. flexneri. The experiments in this proposal seek to identify and characterize the defect in MHC-I processing and/or presentation that occurs during S. flexneri infection. Specifically: 1) using biochemical assays, we will analyze the MHC-I pathway during Shigella infection to determine if there is inhibition of specific activities; and 2) we will use two parallel genetic screens to identify S. flexneri gene product(s) responsible for the inhibition. Through these experiments, we expect to identify and describe the activity of a bacterial inhibitor of MHC-I processing and presentation. Such an inhibitor might represent a novel class of virulence determinants specifically able to inhibit pathogen recognition by the adaptive immune system of the host. Understanding how this inhibition affects bacterial virulence and acquired immunity will further our understanding of the complex interaction of this bacterial pathogen and its mammalian host. PERFORMANCE SITE ========================================Section End===========================================