: CD8+ T cells are crucial to the control of T. cruzi infection and may also hold the key to the development of clinical disease in the chronic Chagas'disease. The goals of this project are to better understand the mechanisms important in the generation of anti-T, cruzi CD8+ T cell responses, to identify the primary and most important targets of these responses, and to obtain a better understanding of why these responses are slow to develop relative to CD8+ T cell responses to other pathogens. A combination of proteomic, expression profiling and bioinformatic tools and information will be used to identify targets of the CD8+ T cell response and the status of each of at least 50 such selected proteins will be tested in ELISPOT, in vivo CTL and eventually MHC Tetramer staining assays. We will investigate two aspects of the generation of CD8+ T cell responses in T. cruzi that might account for the differences between the response generated in this infection and that observed in other better-studied models: the initial encounter of T. cruzi with DC and the antigen presentation function of these DC, and the effect of epitope density on activation of anti-T. cruzi CD8+ T cells. Parasites will be followed from the point of infection to their encounter and activation of naive CD8+ T cells in the lymph node draining the site of infection. Additionally parasite lines will be produced which vary in the level of expression of model epitopes to determine if epitope density plays a role in the rate of generation and the quality and quantity of the CD8+ T cell response to peptides from T. cruzi. Finally, the potential role of altered peptide ligand antagonism by peptides encoded by members of the T. cruzi trans-sialidase gene family in the regulation of CD8+ T cell responses in T. cruzi will be determined and the biological significance of the effect of this antagonism of the generation and effector function of CD8+ T cells will be determined.
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