CD4+ T Cell Receptors in Leishmaniasis

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DESCRIPTION (provided by the applicant): Effector immunity is mediated largely by cytokines, products of innate and differentiated adaptive T cells that orchestrate both host defense and immunopathology. Much research in immunology has focused on cells in lymphoid organs or during in vitro differentiation. Current interest has increasingly focusing on peripheral tissues, where effector cells carry out their functions. Using mice with knock-in constructs that faithfully record cytokine transcripts, we find that naive helper T cells, when polarized to express specific cytokines, maintain IL-4 and IFN-gamma transcripts in an untranslated state in the cell, which we define as 'poised'. Reactivation leads to rapid translation of the previously transcribed message, facilitating rapid and flexible responses. This proposal seeks to define the extent to which priming of normal naive T cells establishes such a 'poised' effector state at the level of cytokine transcripts; to investigate mechanisms that contribute to maintaining the 'poised' state; and to use well-characterized murine parasite infection models - including Nippostrongylus brasiliensis and Leishmania major - to establish whether the relevant pathways exist in vivo. The proposal will use a variety of genetically modified mice together with molecular and biochemical assays to establish whether the process used by differentiating T cells is scaffolded onto more general cellular pathways for coordinating translation with fluctuating levels of protein secretion. Findings made in naive and differentiated helper T cells will be compared with effector cell populations that are resident in tissues, including NK cells, NK T cells and eosinophils. Such analysis may allow broad comparisons between different cell types that activate the IFN-gamma gene, the IL-4 gene, or both genes, potentially revealing core genetic programs linked intimately with effector function in the immune system.