Dissecting the role of CD8+ T cells in atherosclerosis

项目摘要 动脉粥样硬化性心血管疾病（ACVD）是全球死亡和残疾的主要原因， 最佳治疗的患者。虽然许多免疫细胞类型对动脉粥样硬化的影响是很好的- 尽管已经建立了CD 8 + T细胞，但CD 8 + T细胞对疾病病理学的贡献仍有待进一步阐明。在 以前的工作使用无偏单细胞（sc）分析来研究人类的免疫组成， 动脉粥样硬化斑块，我们发现新的失调组织驻留记忆（TRM）CD 8 + T细胞相关 临床CV结局。CD 8 + T细胞浸润在早期和晚期人类中均有描述。 动脉粥样硬化斑块和它们的细胞毒性效应物功能有助于小鼠中的斑块进展。 然而，关于CD 8 + T细胞如何促进动脉粥样硬化斑块脆弱性和心血管疾病的信息， (CV)事件是有限的，仍有待充分了解。在初步的sc研究中，我们发现 转录调节因子Zeb 2作为斑块CD 8 + T细胞致动脉粥样硬化的最佳候选主调节因子 改变。我们假设Zeb 2是效应TRM CD 8 + T细胞活化和细胞毒性的关键驱动因素， 这些改变有助于疾病进展和斑块形成， 易损性.我们还认为其下调与PD-1+ TRM CD 8 + T细胞的重编程有关。 近期中风患者的斑块中发现的细胞。我们提出了两个独立的目标来研究的作用， Zeb 2在斑块易损性和CV事件中的作用在目标1中，我们将剖析Zeb 2介导的斑块激活 TRM CD 8 + T细胞，并确定其与病理斑块脆弱性的关联。在这一目标中，我们还将 确定在活化的TRM CD 8+中选择性缺乏Zeb 2对小鼠动脉粥样硬化的影响。在目标2中， 我们将确定Zeb 2如何介导TRM CD 8 + T细胞失调的不良CV结果，并确定 所有CD 8 + T细胞中Zeb 2下调如何影响它们的耗竭重编程以及这些是否 改变有助于体内斑块大小和易损性。这些研究将解决以下方面的重要差距： 在动脉粥样硬化CD 8 + T细胞生物学的知识，并将解决以前不受重视的细胞和 与斑块破裂/糜烂相关的分子机制可能导致临床CV结局。 我们预见，这些信息可能有助于指导未来设计精确的，分子靶向的 免疫疗法预防颈动脉和冠状动脉疾病患者的CV结局。

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ACVD) is the leading cause of mortality and disability worldwide, even in optimally treated patients. While the impact of many immune cell types on atherosclerosis is well- established, the contribution of CD8+ T cells to the disease pathology remains to be further elucidated. In previous work using unbiased single-cell (sc) analyses to study the immune composition of human atherosclerotic plaques we found new dysregulations tissue resident memory (TRM) CD8+ T cells associated with clinical CV outcomes. CD8+ T cell infiltrates have been described in both early and advanced human atherosclerotic plaques and their cytotoxic effector functions contribute to plaque progression in mice. However, information on how CD8+ T cells contribute to atherosclerotic plaque vulnerability and cardiovascular (CV) events is limited and remains to be fully understood. In preliminary sc studies, we identified the transcriptional regulator Zeb 2 as a top candidate master regulator of plaque CD8+ T cell proatherogenic alterations. We hypothesize that Zeb2 is a key driver of the activation and cytotoxicity of effector TRM CD8+ T cells in atherosclerotic plaques and that these alterations contribute to disease progression and plaque vulnerability. We also contend that its downregulation is implicated in the reprogramming of PD-1+ TRM CD8+ T cells found in plaques of patients with recent stroke. We propose two independent aims to study the role of Zeb2 in plaque vulnerability and CV events. In Aim 1, we will dissect the Zeb2-mediated activation of plaque TRM CD8+ T cells and determine their association with plaque vulnerability at pathology. In this Aim we will also determine the effect of Zeb2 deficiency selectively in activated TRM CD8+ on atherosclerosis in mice. In Aim 2, we will identify how Zeb2 mediates TRM CD8+ T cell dysregulations of adverse CV outcomes and determine how Zeb2 downregulation in all CD8+ T cell affect their exhaustion reprogramming and whether these alterations contribute to plaque size and vulnerability in vivo. These studies will address important gaps in knowledge in CD8+ T cell biology in atherosclerosis, and will tackle previously unappreciated cellular and molecular mechanisms associated with plaque rupture/erosion that may contribute to clinical CV outcomes. We foresee that this information may help guide the future design of precise, molecularly targeted immunotherapies to prevent CV outcomes in patients with carotid and coronary disease.