Immunity to the protozoan Trypanosoma cruzi is complex, involving multiple immune effector mechanisms operating at several levels of the infection. In this study we propose to continue investigation of how immunity to T. cruzi is regulated, with special focus on the. generation, development and maintenance of T cell responses, particularly CD8+ T cell responses which are crucial to the recognition and control of T. cruzi at the level of the infected host cell. Using a panel of newly identified immunodominant and subdominant epitopes from trans-sialidase proteins and MHC-peptide tetramers recognizing the T cells specific for these epitopes, as well as methods for the monitoring of the overall T. cruzi-specific T cell response, we will follow the very earliest events in the development of parasite-specific T cells in an attempt to determine why initial generation of these responses is delayed until 8-10 days post-infection. A complete analysis of the frequency, phenotype and functional activity of parasite-specific T cells, with a strong emphasis on the CDS T cells, will also be conducted with the ultimate goal of determining if parasite persistence leads to a stable effector/memory population or to a state of """"""""antigen-addicted exhaustion"""""""". A newly developed drug treatment/cure model will be used to compare the status of immunological memory that develops in the presence and absence of parasite persistence. The mechanisms by which T. cruzi -specific CD8+ T cells are regulated in muscle tissue will be investigated, highlighting the possible role of PD-1/PD-L1 induced immunoregulation, the trafficking of T cells to muscle, and the role of antigen exposure in T cell suppression/ exhaustion in muscle and other sites of antigen persistence. Lastly the potential to use boosting of immunodominant or subdominant epitope-specific CD8+ T cell responses to achieve better control and perhaps cure of the infection will be investigated. Because of our ability to follow true parasite specific responses in vivo and directly ex vivo and from the very earliest time point into the chronic disease state, these studies will be unique among parasite systems. The results of these studies also have strong parallels with human T. cruzi infection and implications for possible treatment of infection and disease in infected subjects. ? ? ?
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