Dissecting the role of CD8+ T cells in atherosclerosis

剖析 CD8 T 细胞在动脉粥样硬化中的作用

• 批准号: 10630050
• 负责人: Chiara Giannarelli
• 金额: $ 66.55万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630050
• 关键词: Acute; Affect; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Biological Models; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Cardiovascular system; Carotid Artery Plaques; Carotid Endarterectomy; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cellular biology; Clinical; Complement; Coronary Arteriosclerosis; Coronary heart disease; Data; Disease; Disease Progression; Disease model; Down-Regulation; Event; Frequencies; Future; Genes; Genetic Polymorphism; Genetic Transcription; Goals; Granzyme; High Fat Diet; Histologic; Human; ID2 gene; Immune; Immunotherapy; Knowledge; Link; Mediating; Medicine; Memory; Molecular; Molecular Target; Mus; Myocardial Infarction; Nature; Organ Donor; Outcome; Pathologic; Pathology; Patients; Phenotype; Proteins; Public Health; Publishing; Regulation; Rest; Role; Rupture; Signal Pathway; Stroke; Surgical margins; T cell infiltration; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Variant; Work; cell type; cytotoxic; cytotoxicity; design; disability; effector T cell; exhaust; exhaustion; experience; genome-wide analysis; healing; human data; in vivo; innovation; mortality; prevent; programmed cell death protein 1; protein biomarkers; residence; risk variant; single cell analysis; single-cell RNA sequencing; stroke patient; tissue resident memory T cell; transcription factor

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.

项目总结 动脉粥样硬化性心血管疾病(ACVD)是世界范围内死亡和残疾的主要原因，甚至 在接受最佳治疗的患者中。虽然许多免疫细胞类型对动脉粥样硬化的影响是很好的- CD8+T细胞在疾病病理中的作用有待进一步阐明。在……里面 以前的工作是使用无偏的单细胞分析来研究人类的免疫成分。 动脉粥样硬化斑块我们发现新的失调组织驻留记忆(TRM)CD8+T细胞相关 与临床CV结果相关。CD8+T细胞浸润在早期和晚期人类中都有描述 动脉粥样硬化斑块及其细胞毒性效应功能促进了小鼠斑块的发展。 然而，关于CD8+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 (简历)活动是有限的，仍有待充分了解。在初步的SC研究中，我们确定了 转录调控因子Zeb-2作为斑块CD8+T细胞致动脉粥样硬化的首选主调控因子 改装。我们推测ZEB2是TRM CD8+T细胞活化和细胞毒作用的关键驱动因素 动脉粥样硬化斑块中的细胞，这些变化有助于疾病的进展和斑块 脆弱性。我们还认为它的下调与PD-1+TRM CD8+T细胞的重新编程有关 在最近中风患者的斑块中发现了细胞。我们提出了两个独立的目标来研究 斑块易感性和心血管事件中的ZEB2。在目标1中，我们将剖析ZEB2介导的斑块激活 TRM CD8+T细胞，并在病理上确定它们与斑块脆弱性的关系。在这一目标中，我们还将 检测选择性激活的TRM CD8+中ZEB2缺乏对小鼠动脉粥样硬化的影响。在目标2中， 我们将确定ZEB2如何介导TRM CD8+T细胞对不良心血管结局的调节，并确定 所有CD8+T细胞中ZEB2的下调如何影响其衰竭重编程，以及这些 在活体内，斑块的大小和脆弱性都是由斑块的改变引起的。这些研究将解决以下方面的重要差距 在动脉粥样硬化的CD8+T细胞生物学方面的知识，并将解决以前未被重视的细胞和 与斑块破裂/侵蚀相关的分子机制可能有助于临床心血管预后。 我们预见，这些信息可能有助于指导未来精确的、分子靶向的设计 预防颈动脉和冠状动脉疾病患者发生心血管事件的免疫疗法。

项目成果

The IRG1-itaconate axis protects from cholesterol-induced inflammation and atherosclerosis.

IRG1-衣康酸轴可防止胆固醇引起的炎症和动脉粥样硬化。

• DOI: 10.1073/pnas.2400675121
• 发表时间: 2024
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Cyr,Yannick;Bozal,FazliK;BarciaDurán,JoséGabriel;Newman,AlexandraAC;Amadori,Letizia;Smyrnis,Panagiotis;Gourvest,Morgane;Das,Dayasagar;Gildea,Michael;Kaur,Ravneet;Zhang,Tracy;Wang,KristinM;VonItter,Richard;Schlegel,PMarti
• 通讯作者: Schlegel,PMarti

How Single-Cell Technologies Have Provided New Insights Into Atherosclerosis.

• DOI: 10.1161/atvbaha.121.315849
• 发表时间: 2022-03
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Eberhardt N;Giannarelli C
• 通讯作者: Giannarelli C

Single-cell profiling reveals inflammatory polarization of human carotid versus femoral plaque leukocytes.

• DOI: 10.1172/jci.insight.171359
• 发表时间: 2023-09-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Slysz, Joshua;Sinha, Arjun;Deberge, Matthew;Singh, Shalini;Avgousti, Harris;Lee, Inhyeok;Glinton, Kristofor;Nagasaka, Reina;Dalal, Prarthana;Alexandria, Shaina;Wai, Ching Man;Tellez, Ricardo;Vescovo, Mariavittoria;Sunderraj, Ashwin;Wang, Xinkun;Schipma, Matthew;Sisk, Ryan;Gulati, Rishab;Vallejo, Jenifer;Saigusa, Ryosuke;Lloyd-Jones, Donald M.;Lomasney, Jon;Weinberg, Samuel;Ho, Karen;Ley, Klaus;Giannarelli, Chiara;Thorp, Edward B.;Feinstein, Matthew J.
• 通讯作者: Feinstein, Matthew J.

Single-Point Vulnerabilities in Atherosclerotic Plaque.

动脉粥样硬化斑块中的单点漏洞。

• DOI: 10.1016/j.jacc.2023.05.001
• 发表时间: 2023
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Giannarelli,Chiara