Control of CD8+ effector T cell Differentiation

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DESCRIPTION (provided by applicant): Cell-mediated immunity is critical for host defense against all classes of pathogens and cells that have undergone cancerous transformation. Strategies to vaccinate or potentiate T lymphocyte-mediated cellular immunity have been remarkably ineffective, probably owing to our limited understanding of the mechanisms for establishing and maintaining T cell effector function and memory. This proposal investigates the transcriptional mechanisms contributing to the formation of cellular immunity. Preliminary evidence is offered in support of a model that the molecular signatures of both CD8+ effector and memory T cells are regulated by a paralogous set of transcription factors from the T-box family of genes, Eomesodermin and T-bet. Either the redundant, concerted, or exclusive action of these two transcription factors may be essential for induction of cellular immunity and memory in both CD4+ and CD8+ T cells. This proposal aims to further define the role of Eomesodermin during CD8+ T cell effector and memory differentiation, in vitro and in vivo. Studies will be undertaken to define the precise contribution of Eomesodermin and T-bet in inducing lineage-restricted characteristics of effector T cells using modeled differentiation in vitro. Use of in vivo models of infectious diseases, including challenges with Listeria monocytogenes and Lymphocytic Choriomeningitis Virus, will be used to characterize the dynamic patterns of expression of Eomesodermin and T-bet, and determine whether these 2 factors play a causal role in promoting effector function, durable immunity, and memory T cell generation. Successful execution of the 3 specific aims of this proposal should provide new insight into the mechanisms of gene induction and cellular differentiation in immune response. It is also anticipated that these studies will yield new strategies for defending us against a variety of infectious diseases that are the focus of our CD8+ T cell responses.