CD1-restricted T cell response in atherosclerosis

描述(由申请人提供)： 分化蛋白簇(CD1)代表了一类新的 抗原递呈分子，其结构类似于MHC I类 抗原，并可能限制某些T淋巴细胞对脂质的反应 抗原。有五个CD1编码的两组CD1分子 基因(CD1a、b、c、d和e)。动脉粥样硬化病变包含大量T细胞 细胞和CD1阳性的巨噬细胞和树突状细胞 化学修饰的脂类(例如，胆固醇氧化物或氧化甾醇和 氧化的磷脂)存在于氧化脂蛋白中，提高了 CD1限制性T细胞可能存在于皮损和 对局部巨噬细胞呈递的致动脉粥样硬化脂质抗原的反应 树突状细胞。这项提案的具体目标是确定 (1)CD1亚型表达及CD1限制性T细胞应答 氧化的脂蛋白在动脉粥样硬化中的脂组成； CD1突变或多态与血管病变的相关性 系统性红斑狼疮和动脉粥样硬化患者的自身免疫；(3)细胞因子 CD1d限制性NK T细胞的产生及其促凋亡功能 对脂类抗原有反应；以及(4)敲除CD1d的影响 T细胞对脂类抗原反应的基因与肿瘤的发生 载脂蛋白E缺乏引起的动脉粥样硬化。实验性的 程序包括分析T细胞细胞因子的产生和 抗原受体图谱、T细胞对CD1-的反应 脂质复合体，CD1基因基因组DNA序列的评估， 动脉粥样硬化性病变的组织病理学特征 新近建立的CD1/载脂蛋白E双基因敲除小鼠 我们的实验室。该项目的完成预计将产生 有助于了解免疫机制的有价值的信息 动脉粥样硬化形成过程中潜在的血管损伤。

DESCRIPTION (provided by applicant): 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.