The cluster of differentiation I (CD1) proteins represent a new class of antigen-presenting molecules, which structurally resemble MHC class I antigens and may restrict certain T lymphocyte responses to lipid antigens. There are two groups of CD1 molecules encoded by five CD1 genes (CD1a, b, c, d and e). Atherosclerotic lesions contain numerous T cells and CD1-positive macrophages and dendritic cells in addition to chemically modified lipids (e.g., cholesterol oxides or oxysterols and oxidized phospholipids) present in oxidized lipoproteins, raising the possibility that CD1-restricted T cells may exist in the lesions and respond to atherogenic lipid antigens presented by local macrophages and dendritic cells.
The specific aims of this proposal are to determine (1) the CD1 isotype expression and CD1-restricted T cell response to lipid components of oxidized lipoproteins in atherosclerosis; (2) the association of an CD1 mutation or polymorphism with altered vascular autoimmunity in patients with SLE and atherosclerosis; (3) the cytokine production and pro-apoptotic function of CD1d-restricted NK T cells that are reactive to lipid antigens; and (4) the impact of knocking out CD1d gene on the T cell responses to lipid antigens and the development of atherosclerosis caused by apolipoprotein-E deficiency. The experimental procedures involve the analysis of T cell cytokine production and antigen receptor profiles, the evaluation of T cell response to CD1- lipid complexes, the assessment of genomic DNA sequences for CD1 genes, and the histopathological characterization of atherosclerotic lesions in the CD1/apolipoprotein-E double knockout mice recently established in our lab. Accomplishment of this project is anticipated to generate valuable information that help understand the immune mechanisms underlying vascular injury during atherogenesis.
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