T Regulatory Lymphocytes, HDL Function, and Atherosclerosis

T 调节性淋巴细胞、HDL 功能和动脉粥样硬化

基本信息

批准号：
9054901
负责人：
Catherine C Hedrick
金额：
$ 69.25万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
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：
2013-06-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9054901
关键词：
Antigen Presentation Aorta Apolipoprotein A-I Apolipoprotein E Apolipoproteins Atherosclerosis Binding Biological Preservation Blood Circulation CD4 Positive T Lymphocytes Cell physiology Cells Cholesterol Dendritic Cells Diet Disease Emigrations Equilibrium Flow Cytometry G-Protein-Coupled Receptors Generations Goals H218 Protein Health High Density Lipoproteins Homeostasis Immune Immune Tolerance Immunity In Vitro Incubated Inflammatory Interferons Interleukin-17 Knockout Mice Link Lipoprotein Binding Lymphocyte Lymphocyte Count Lymphocyte Function Lysophospholipids Mus Peripheral Phenotype Plasma Play Production Proteins Receptor Signaling Recombinants Regulatory T-Lymphocyte Reporter Role Signal Pathway Signal Transduction Sphingosine-1-Phosphate Receptor T-Lymphocyte Testing Therapeutic Transgenic Organisms Tretinoin Work adaptive immunity atherogenesis atheroprotective base cytokine edg-1 Protein hypercholesterolemia in vivo in vivo Model insight lipid mediator macrophage novel reverse cholesterol transport sphingosine 1-phosphate

项目摘要

DESCRIPTION (provided by applicant): T regulatory lymphocytes (Treg) maintain immune tolerance by suppressing both innate and adaptive immune cells. Tregs are atheroprotective, yet Treg phenotypes and function are disturbed during atherosclerosis progression. High-density lipoproteins (HDL) are atheroprotective, in large part due to their function in reverse cholesterol transport. However, HDL also performs cholesterol-independent functions, including the transport of sphingosine-1-phosphate (S1P), an important lipid mediator of immunity. Apolipoprotein M, found on HDL, binds S1P to aid in delivery of S1P to cells in the vasculature, including cells involved in adaptive immunity. Based upon our work and that of others, S1P most likely acts to impart differential effects on cytokine production by dendritic cells and lymphocyte depending on the microenvironment. We hypothesize that a novel function of HDL in adaptive immunity is related to the ability of HDL to stabilize Treg homeostasis and suppressive activity in vivo during atherogenesis. We will test our hypotheses in 2 specific aims. Specific Aim 1 will test the hypothesis that HDL regulates Treg homeostasis in atherosclerosis through S1P action. Specific Aim 2 will identify mechanisms for how HDL-S1P impacts both cell-autonomous dendritic cell and Treg actions to preserve Treg function in atherosclerosis.

描述（由申请人提供）：T调节性淋巴细胞（TREG）通过抑制先天和适应性免疫细胞来保持免疫耐受性。 Treg是动脉保护性的，但是在动脉粥样硬化进展过程中，Treg表型和功能受到干扰。高密度脂蛋白（HDL）是动脉保护剂，这在很大程度上是由于它们在反向胆固醇转运中的功能。但是，HDL还执行非胆固醇非依赖性功能，包括鞘氨醇1-磷酸（S1P）的转运，这是免疫力的重要脂质介质。在HDL上发现的载脂蛋白M结合S1P，有助于将S1P递送到脉管系统中的细胞，包括参与适应性免疫的细胞。基于我们的工作和其他工作，S1P最有可能起作用，以树突状细胞和淋巴细胞对细胞因子产生的差异作用，具体取决于微环境。我们假设HDL在自适应免疫中的新功能与HDL稳定Treg稳态和抑制活性的能力有关动脉粥样硬化期间的体内。我们将以2个特定目标来检验我们的假设。具体目标1将测试 HDL通过S1P作用调节动脉粥样硬化中TREG稳态的假设。具体目标2将确定HDL-S1P如何影响细胞自治的树突状细胞和Treg作用的机制，以保留动脉粥样硬化中Treg功能。