CELL MEDIATED IMMUNE MECHANISM IN ATHEROGENESIS

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DESCRIPTION (provided by applicant): The atherosclerotic lesion is a site of chronic inflammation, and there is ample evidence that the innate and adaptive immune responses drive this inflammatory process. Activated interferon-gamma secreting Thl lymphocytes are early and persistent residents of the atheroma, but several important questions about their presence are not resolved. The guiding hypotheses for these studies are that Thl cells are selectively recruited into atheromata, they are specifically activated by antigen and costimulators presented by the macrophage-foam cell, and as a result of activation, the Thl cells promote the inflammatory pathology of arterial lesions. This project will focus on the mechanisms of T lymphocytes recruitment, activation, and effector functions at the site of atherosclerotic lesions, under three Specific Aims. The First Specific Aim will address mechanisms of T cell recruitment to atheromata. Intravital microscopic techniques, and TCR transgenic T cell populations will be used to define the molecular interactions regulating T cell subset specific interactions with atherosclerotic lesions in isolated perfused mouse carotid arteries. Complementary experiments employing a newly developed coculture system will define how T cell-endothelial interactions are influenced by anatomically juxtaposed macrophage foam cells. The Second Specific Aim will examine activation of T cells, with a focus on the immune functions of the macrophage-derived foam cell. Studies will examine ways in which lipid-uptake and accumulation influences macrophage antigen processing and presentation pathways, macrophage costimulation of T cells, and secretion of cytokines that influence T cells. In the Third Specific Aim, the effects of T cell activation on atherosclerosis will be addressed. The role of costimulatory pathways and IFNgamma production in T cell responses to plaque antigens will be studied in compound mutant mouse lines. In addition, a mouse line expressing a model antigen on endothelial cells will be developed and used to define how effector and regulatory T cells specific for that antigen influence the development of atherosclerosis. The results of these studies should enhance our understanding of the inflammatory nature of atherosclerosis, and suggest strategies for therapeutic immumodulation of this disease.