The Role of Group 1 CD1-Restricted T Cells in Atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种复杂的炎症性疾病，其特征在于血管壁内脂质的滞留和改变。 最近，不同的T细胞亚群在动脉粥样硬化的发展中的作用已被评估。 一种特定的T细胞亚群识别由抗原呈递分子的CD 1家族呈递的脂质抗原。 在人类中，该家族由第1组CD 1分子CD 1a、B和c以及第2组分子CD 1d组成。 小鼠缺乏第1组CD 1，但表达CD 1d。 CD 1的独特结合特异性表明CD 1分子在向参与动脉粥样硬化形成的T细胞呈递修饰的脂质中具有潜在作用。 事实上，CD 1d限制性不变NKT细胞已被证明在动脉粥样硬化小鼠模型中发挥促动脉粥样硬化作用。 此外，已在人类中发现的动脉粥样硬化斑块中观察到第1组CD 1的表达水平升高，并且第1组CD 1限制性T细胞可在体外被巨噬细胞来源的泡沫细胞激活。 虽然这些发现表明，第1组CD 1分子和它们的同源T细胞有助于这种疾病的发病机制，但第1组CD 1限制性T细胞的功能性作用可能与其自身免疫功能有关。 由于缺乏合适的动物模型，尚未直接研究动脉粥样硬化中的T细胞。 为了克服这一限制，我的实验室已经产生了转基因小鼠模型，表达人类1组CD 1分子和1组CD 1特异性T细胞受体。 在这项研究中，我们建议利用这些新的转基因小鼠模型来测试的假设，组1 CD 1-限制性T细胞有助于动脉粥样硬化。 在目的1中，我们建议在饮食诱导的动脉粥样硬化模型中确定第1组CD 1限制性反应对动脉粥样硬化形成的总体贡献，并研究第1组CD 1限制性自身反应性T细胞对疾病发病机制的作用。 在目的2中，我们建议检查是否高血压疾病与动脉粥样硬化影响组1 CD 1-限制性T细胞的激活和功能，以及介导这种影响的机制。 总的来说，这些研究将使我们更好地了解第1组CD 1限制性自身反应性T细胞如何促进动脉粥样硬化，以及它们是否可以被操纵来调节疾病的进展。

DESCRIPTION (provided by applicant): Atherosclerosis is a complex inflammatory disease characterized by the retention and modification of lipids within the vascular wall. Recently, the role of distinct T cell subsets in the development of atherosclerosis has been evaluated. One particular T cell subsets recognizes lipid antigens presented by CD1 family of antigen presenting molecules. In humans, this family consists of the group 1 CD1 molecules CD1a, b, and c, and the group 2 molecule CD1d. Mice lack group 1 CD1, but express CD1d. The unique binding specificity of CD1 suggests a potential role for the CD1 molecules in the presentation of modified lipids to T cells involved in atherogenesis. Indeed, CD1d-restricted invariant NKT cells have been shown to play a proatherogenic role in murine models of atherosclerosis. Moreover, elevated expression levels of group 1 CD1 have been observed in atherosclerotic plaques found in humans, and group 1 CD1-restricted T cells can be activated by macrophage-derived foam cells in vitro. While these findings suggest that group 1 CD1 molecules and their cognate T cells contribute to the pathogenesis of this disease, the functional role of group 1 CD1-restricted T cells in atherosclerosis has not been directly studied due to the lack of a suitable animal model. To overcome this limitation, my lab has generated transgenic mouse models that express both the human group 1 CD1 molecules and group 1 CD1-specific T cell receptors. In this study, we propose to utilize these novel transgenic mouse models to test the hypothesis that group 1 CD1-restricted T cells contribute to atherogenesis. In Aim 1, we propose to determine the overall contribution of group 1 CD1-restricted responses to atherogenesis in a diet-induced atherosclerosis model and to investigate the mechanisms by which group 1 CD1-restricted autoreactive T cells contribute to disease pathogenesis. In Aim 2, we propose to examine whether hyperlipidemic conditions associated with atherosclerosis affect the activation and function of group 1 CD1-restricted T cells, as well as the mechanisms mediating such effects. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted autoreactive T cells contribute to atherosclerosis and whether they can be manipulated to modulate the progression of the disease.