Regulation of T Cell Responses in Atherosclerosis

动脉粥样硬化中 T 细胞反应的调节

• 批准号: 7568264
• 负责人: ANDREW H LICHTMAN
• 金额: $ 47.15万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-12 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568264
• 关键词: Acute; Address; Adoptive Transfer; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Arterial Fatty Streak; Asses; Atherosclerosis; Autoimmunity; Binding; Biological Assay; Bone Marrow; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Cellular Immunity; Chimera organism; Cholesterol; Chronic; Clinical; Collagen; Cultured Cells; Data; Development; Disease; Disease Progression; Endothelial Cells; Equilibrium; Family; Goals; Heat shock proteins; Hematopoietic; Immune response; Immunohistochemistry; In Vitro; Inflammation; Interferons; Interleukin-2; Knowledge; Laboratories; Lead; Lesion; Ligands; Lipoproteins; Lymphoid Tissue; Mediating; Mediator of activation protein; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Phenotype; Population; Production; Publishing; Regulation; Regulatory Pathway; Reporter; Research Personnel; Role; Signal Transduction; Smooth Muscle Myocytes; Syndrome; T cell regulation; T-Lymphocyte; T-bet protein; Th1 Cells; Therapeutic; Transgenes; Work; atheroprotective; cell mediated immune response; cell type; cytokine; hypercholesterolemia; immunoregulation; in vivo; member; microbial; mortality; mouse model; oxidized low density lipoprotein; programs; receptor; response

DESCRIPTION (provided by applicant): Chronic inflammation is a fundamental component of atherosclerosis, and is promoted by T-cells specific for antigens within lesions. Work in the applicant's laboratory has established the importance Th1 cell differentiation and B7-family costimulators to pro-atherogenic T cell responses. Although there have been important recent advances in the field of T cell regulation, there has been little application of this knowledge to atherosclerosis. Our preliminary data indicate that there are systemic changes in regulatory T cells (Treg) in the setting of hypercholesterolemia, and there is a potentially important connection between the T cell costimulatory molecule ICOS and Treg activity. The objective of this proposal is to achieve a better understand of the regulatory pathways that can limit pro-atherogenic T cell responses. Three specific Aims are proposed. In Aim 1, we will determine if and how regulatory T cells (Treg) influence pro-atherogenic effector T cells responses and lesion development. We hypothesize that hypercholesterolemia leads to enhancement of both effector CD4+ T cell responses and compensatory systemic Treg responses. Treg will be enumerated in lymphoid tissue and lesions in LDLR KO mice, including FoxP3-GFP/LDLR reporter mice. Functional assays will be performed on Treg isolated from LDLR KO mice, and Treg effects on atherosclerosis and CD4+ T cell responses to atheroantigens will be examined by in vivo adoptive transfer and depletion studies. In Aim 2, we will characterize the mechanisms by which the ICOS on T cells regulates atherosclerotic lesion development and maturation. We hypothesize that ICOS exerts an atheroprotective role by enhancing Treg-mediated suppression of plaque-antigen specific effector T cells and/or by skewing the effector phenotype of plaque-antigen specific effector T cells. We will analyze extent and phenotype of lesions, as well as effector and Treg responses to atheroantigens, in ICOS and ICOS ligand deficient LDLR KO mice. Bone marrow chimeras, and double KO mice will be employed. In Aim 3, we will determine if the PD-L1/PD-L2L-PD-1 T cell regulatory pathway influences the development of atherosclerosis and associated T cell responses. We hypothesize that PD-L1 and/or PD-L2, expressed on bone marrow derived antigen presenting cells or on endothelial cells bind to PD-1 on T cells and function to limit T cell responses to atheroantigens. We will employ LDLR KO mice deficient in PD-L1 and PD-L2 or PD-1, using bone marrow chimeras, and compound KO mice. Atherosclerosis remains a major cause of morbidity and mortality throughout the world. Successful completion of the Aims in this proposal will lead to a better understanding of how immune responses that aggravate atherosclerotic disease may be therapeutically controlled.

描述（由申请人提供）：慢性炎症是动脉粥样硬化的基本组成部分，由病变内特异性抗原的t细胞促进。申请人实验室的工作已经确定了Th1细胞分化和b7家族共刺激剂对促粥样硬化T细胞反应的重要性。尽管最近在T细胞调节领域取得了重要进展，但在动脉粥样硬化方面的应用很少。我们的初步数据表明，在高胆固醇血症的情况下，调节性T细胞（Treg）存在全身性变化，T细胞共刺激分子ICOS与Treg活性之间存在潜在的重要联系。本建议的目的是为了更好地理解可以限制促粥样硬化T细胞反应的调控途径。提出了三个具体目标。在目的1中，我们将确定调节性T细胞（Treg）是否以及如何影响促动脉粥样硬化效应T细胞反应和病变发展。我们假设高胆固醇血症导致效应CD4+ T细胞反应和代偿性全身Treg反应的增强。在LDLR KO小鼠（包括FoxP3-GFP/LDLR报告小鼠）的淋巴组织和病变中，将列举Treg。将对从LDLR KO小鼠中分离的Treg进行功能分析，Treg对动脉粥样硬化和CD4+ T细胞对动脉粥样硬化抗原的反应的影响将通过体内过继转移和消耗研究进行检验。在Aim 2中，我们将描述T细胞上的ICOS调节动脉粥样硬化病变发展和成熟的机制。我们假设ICOS通过增强treg介导的斑块抗原特异性效应T细胞的抑制和/或通过扭曲斑块抗原特异性效应T细胞的效应表型来发挥动脉粥样硬化保护作用。我们将分析ICOS和ICOS配体缺陷的LDLR KO小鼠的病变程度和表型，以及对动脉粥样硬化抗原的效应和Treg反应。骨髓嵌合体和双KO小鼠将被使用。在Aim 3中，我们将确定PD-L1/PD-L2L-PD-1 T细胞调控通路是否影响动脉粥样硬化的发展和相关的T细胞反应。我们假设，在骨髓源性抗原呈递细胞或内皮细胞上表达的PD-L1和/或PD-L2与T细胞上的PD-1结合，并发挥限制T细胞对动脉粥样硬化抗原反应的作用。我们将使用缺乏PD-L1和PD-L2或PD-1的LDLR KO小鼠，使用骨髓嵌合体和复合KO小鼠。