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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要动脉粥样硬化性心血管疾病（ACVD）是全世界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已得到充分证实尽管已确定，但 CD8+ T 细胞对疾病病理学的贡献仍有待进一步阐明。在之前的工作使用无偏单细胞（sc）分析来研究人类的免疫组成我们发现动脉粥样硬化斑块中与组织驻留记忆 (TRM) CD8+ T 细胞相关的新失调与临床心血管结果。 CD8+ T 细胞浸润已在早期和晚期人类中得到描述动脉粥样硬化斑块及其细胞毒性效应器功能有助于小鼠斑块的进展。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 (CV) 事件是有限的，仍有待充分理解。在初步的 SC 研究中，我们确定了转录调节因子 Zeb 2 作为斑块 CD8+ T 细胞致动脉粥样硬化的最佳候选主调节因子变更。我们假设 Zeb2 是效应 TRM CD8+ T 激活和细胞毒性的关键驱动因素动脉粥样硬化斑块中的细胞，这些改变有助于疾病进展和斑块脆弱性。我们还认为其下调与 PD-1+ TRM CD8+ T 的重编程有关在最近中风的患者斑块中发现的细胞。我们提出两个独立的目标来研究 Zeb2 在斑块脆弱性和心血管事件中的作用。在目标 1 中，我们将剖析 Zeb2 介导的斑块激活 TRM CD8+ T 细胞并确定其与病理学斑块脆弱性的关联。为了这个目标，我们还将确定激活的 TRM CD8+ 中选择性 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 如何介导不良 CV 结局的 TRM CD8+ T 细胞失调，并确定所有 CD8+ T 细胞中的 Zeb2 下调如何影响它们的耗竭重编程以及这些是否改变会影响斑块的大小和体内的脆弱性。这些研究将解决以下方面的重要差距：动脉粥样硬化中 CD8+ T 细胞生物学的知识，并将解决以前未认识到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结果。我们预计这些信息可能有助于指导未来精确、分子靶向的设计免疫疗法可预防颈动脉和冠状动脉疾病患者的心血管结局。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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。