T Regulatory Lymphocytes, HDL Function, and Atherosclerosis

描述（由申请人提供）：调节性T淋巴细胞（Treg）通过抑制先天性和适应性免疫细胞来维持免疫耐受。Treg具有动脉粥样硬化保护作用，但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）具有动脉粥样硬化保护作用，这在很大程度上是由于它们在胆固醇逆向转运中的功能。然而，HDL也执行非胆固醇依赖性功能，包括鞘氨醇-1-磷酸（S1 P）的转运，这是一种重要的免疫脂质介质。载脂蛋白M在HDL上发现，结合S1 P以帮助将S1 P递送到脉管系统中的细胞，包括参与适应性免疫的细胞。根据我们的工作和其他人的工作，S1 P最有可能根据微环境对树突状细胞和淋巴细胞产生的细胞因子产生不同的影响。我们假设HDL在获得性免疫中的一种新功能与HDL稳定Treg稳态和抑制Treg活性的能力有关。 在动脉粥样硬化形成过程中。我们将在两个具体目标中测试我们的假设。具体目标1将测试 HDL通过S1 P作用调节动脉粥样硬化中Treg稳态的假说。具体目标2将确定HDL-S1 P如何影响细胞自主树突状细胞和Treg作用的机制，以保护Treg在动脉粥样硬化中的功能。

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.