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

第 1 组 CD1 限制性 T 细胞在动脉粥样硬化中的作用

基本信息

批准号：
8451723
负责人：
Chyung-Ru Wang
金额：
$ 23.18万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451723
关键词：
Adoptive Transfer Affect Animal Model Antigen-Presenting Cells Antigens Apolipoprotein E Arterial Fatty Streak Atherosclerosis Binding Blood Vessels Bone Marrow CD1 Antigens Cells Chimera organism Chronic Complex Development Diet Disease Disease Progression Dyslipidemias Environment Family Fatty acid glycerol esters Foam Cells Frequencies Human Hyperlipidemia Immune Immunity In Vitro Infiltration Inflammatory Kinetics Lead Lesion Leukocytes Lipids Low Density Lipoprotein Receptor MHC Class I Genes Mediating Modeling Modification Morbidity - disease rate Mus Pathogenesis Pattern Peptides Play Population Proteins Risk Factors Role Serum Specificity Staging T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Intervention Transgenic Mice United States atherogenesis autoreactive T cell congenic cytokine disorder prevention functional status gag Gene Products human tissue in vivo insight macrophage mortality mouse model novel public health relevance response

项目摘要

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.

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，其特征是血管壁内脂质的滞留和改变。最近，人们对不同 T 细胞亚群在动脉粥样硬化发展中的作用进行了评估。一种特定的 T 细胞亚群识别由抗原呈递分子 CD1 家族呈递的脂质抗原。在人类中，该家族由第 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 独特的结合特异性表明 CD1 分子在将修饰的脂质呈递给参与动脉粥样硬化形成的 T 细胞中具有潜在作用。事实上，CD1d 限制的不变 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，在人类动脉粥样硬化斑块中观察到1组CD1表达水平升高，并且1组CD1限制性T细胞可以在体外被巨噬细胞衍生的泡沫细胞激活。虽然这些发现表明第 1 组 CD1 分子及其同源 T 细胞有助于这种疾病的发病机制，但第 1 组 CD1 限制性的功能作用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，我的实验室构建了表达人类 1 类 CD1 分子和 1 类 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型转基因小鼠模型来检验第 1 组 CD1 限制性 T 细胞导致动脉粥样硬化的假设。在目标 1 中，我们建议确定饮食诱导的动脉粥样硬化模型中第 1 组 CD1 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 CD1 限制性自身反应性 T 细胞促成疾病发病机制的机制。在目标 2 中，我们建议检查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，以及介导这种影响的机制。总的来说，这些研究将有助于更好地了解第 1 组 CD1 限制性自身反应性 T 细胞如何导致动脉粥样硬化，以及是否可以操纵它们来调节疾病的进展。