Regulation of T Cell Responses in Atherosclerosis

描述(由申请人提供)：令人信服的证据支持炎症对动脉粥样硬化病变的发展以及与不稳定病变相关的灾难性临床事件有重大贡献的假设。来自人类和小鼠研究的大量证据表明，T淋巴细胞在推动动脉粥样硬化性疾病的炎症中发挥着重要作用。我们实验室的研究表明，调节T细胞免疫的生理机制，包括调节辅助性T细胞亚群分化、共刺激/共抑制途径和调节性T细胞，都显著影响致动脉粥样硬化的T细胞反应。此外，我们已经证实他汀类药物通过上调转录因子KLF2来抑制炎症效应T细胞反应。这些发现是拟议项目的基础，其广泛目标是发现从治疗上改变或阻断动脉中致病T细胞反应的方法。这一目标将通过在体外和体内用小鼠和人的树突状细胞、巨噬细胞和T细胞进行实验来实现。这项工作将被组织成以下三个相互关联的具体目标：1-基于树突状细胞中KLF2的诱导，开发耐受致动脉粥样硬化的T细胞的方法。2-开发在长期高胆固醇血症条件下维持动脉粥样硬化病变中调节性T细胞(Treg)反应的方法。3-确定PD-1介导的抑制致动脉粥样硬化免疫反应的细胞基础。将采取几种实验方法，包括：药物操纵和在易患动脉粥样硬化的小鼠品系之间过继转移树突状细胞；谱系特异性cre-lox介导的调控基因的缺失，包括DC中的KLF2和T细胞和髓样细胞中的PD-1，所有这些都在易患动脉粥样硬化的小鼠中；以及分析胆固醇诱导的先天炎症对Treg活性和表型的影响。在每个目标中提出的工作解决了在动脉粥样硬化性疾病中调节T细胞的不同的基本机制，我们知道这与我们之前的工作相关。这些机制中的每一种都可能影响其他机制，我们将研究这些相互作用。总体而言，所获得的信息将直接与心血管疾病免疫治疗方法的发展相关。 公共卫生相关性：动脉粥样硬化是全球发病率和死亡率的主要原因，是一种部分由T淋巴细胞反应驱动的动脉壁慢性炎症性疾病。这个项目将描述致动脉粥样硬化的T淋巴细胞是如何通过与其他细胞的相互作用来调节的。如果成功，产生的数据将有助于开发新的动脉粥样硬化抗炎治疗方法。

DESCRIPTION (provided by applicant): Compelling evidence supports the hypothesis that inflammation contributes significantly to the development of atherosclerotic lesions and to the catastrophic clinical events associated with unstable lesions. Ample evidence from both human and mouse studies indicate that T lymphocytes play important roles in driving inflammation in atherosclerotic disease. Studies from our laboratory have shown that physiologic mechanisms of regulation of T cell immunity, including modulation of helper T cell subset differentiation, co-stimulatory/co-inhibitory pathways, and regulatory T cells, all significantly impact pro-atherogenic T cell responses. Furthermore, we have established that statins suppress inflammatory effector T cell responses through up-regulation of the transcription factor KLF2. These finding serve as the basis for the proposed project, with the broad objective of discovering ways to therapeutically alter or block the pathogenic T cell responses in arteries. This objective will be pursued through experiments with both mouse and human dendritic cells, macrophages and T cells, both in vitro and in vivo. The work will be organized into the following three interrelated Specific Aims: 1- Develop methods of tolerizing proatherogenic T cells based on induction of KLF2 in dendritic cells. 2- Develop approaches to sustain regulatory T cell (Treg) responses in atherosclerotic lesions under conditions of prolonged hypercholesterolemia. 3- Determine the cellular basis of PD-1 mediated suppression of proatherogenic immune responses. Several experimental approaches will be taken including: pharmacologic manipulation and adoptive transfer of dendritic cells between atherosclerotic-prone mouse strains; lineage specific cre-lox mediated deletion of regulatory genes including KLF2 in DCs and PD-1 in T cells and myeloid cells, all in atherosclerotic-prone mince; and analyses of the effects of cholesterol-induced innate inflammation on Treg viability and phenotype. The work proposed in each Aim address a different basic mechanism of the regulation of T cells in atherosclerotic disease that we know is relevant from our previous work. Each of these mechanisms will likely impact the others, and we will study these interactions. Overall, the information obtained will be of direct translational relevance to the development of immunotherapeutic approaches for cardiovascular disease. PUBLIC HEALTH RELEVANCE: Atherosclerosis, a leading cause of morbidity and mortality worldwide, is a chronic inflammatory disease of the arterial wall driven in part by T lymphocyte responses. This project will characterize how proatherogenic T lymphocytes are regulated through the interaction with other cells. If successful, the data generated will help in development of new anti-inflammatory treatments for atherosclerosis.