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

描述(申请人提供)：动脉粥样硬化是一种复杂的炎症性疾病，其特征是脂类在血管壁内滞留和改变。最近，不同的T细胞亚群在动脉粥样硬化发展中的作用已被评估。一个特殊的T细胞亚群识别由CD1家族抗原提呈分子提呈的脂类抗原。在人类中，这个家族由第1组CD1分子CD1a、b和c以及第2组分子CD1d组成。小鼠缺乏第1组CD1，但表达CD1d。CD1独特的结合特异性提示CD1分子在将修饰的脂类呈递给参与动脉粥样硬化形成的T细胞方面具有潜在的作用。事实上，CD1d限制的不变NKT细胞已被证明在小鼠动脉粥样硬化模型中起到促动脉粥样硬化的作用。此外，在人类动脉粥样硬化斑块中观察到第1组CD1的高表达，体外巨噬细胞来源的泡沫细胞可以激活第1组CD1限制性T细胞。虽然这些发现表明第1组CD1分子和它们的同源T细胞参与了该病的发病，但第1组CD1限制了其功能 由于缺乏合适的动物模型，T细胞在动脉粥样硬化中的作用尚未得到直接研究。为了克服这一限制，我的实验室培育出了同时表达人类第1组CD1分子和第1组CD1特异性T细胞受体的转基因小鼠模型。在这项研究中，我们建议利用这些新的转基因小鼠模型来检验第一组CD1限制性T细胞参与动脉粥样硬化的假设。在目标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CD1限制性反应对动脉粥样硬化形成的总体贡献，并探讨第1组CD1限制性自身反应性T细胞在疾病发病机制中的作用机制。在目标2中，我们建议研究与动脉粥样硬化相关的高脂血症是否影响第1组CD1限制性T细胞的激活和功能，以及调节这种作用的机制。总而言之，这些研究将有助于更好地理解第1组CD1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发展。

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.