Exploring a Novel CD8 T Cell Subset in Cardiovascular Disease Progression and Atherosclerosis

探索心血管疾病进展和动脉粥样硬化中的新型 CD8 T 细胞亚群

• 批准号: 9760997
• 负责人: Lindsey E Padgett
• 金额: $ 4.83万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-31 至 2020-10-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9760997
• 关键词: Adoptive Transfer; Adverse event; Agatston Score; Antigens; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Autoimmune Diseases; Biological Markers; Blood; Blood flow; CD8-Positive T-Lymphocytes; CD8B1 gene; CD95 Antigens; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Chronic; Clinical; Coronary Angiography; Cytometry; Development; Diagnosis; Disease Progression; Event; Fatty acid glycerol esters; Flow Cytometry; Frequencies; Health; High Fat Diet; Human; Immune; Immune System Diseases; Immunologic Markers; Immunologics; Incidence; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Lymphocyte; Memory; Methods; Mouse Strains; Multi-Ethnic Study of Atherosclerosis; Mus; Myocardial Infarction; Outcome; Patients; Phenotype; Population; Population Heterogeneity; Predictive Value; Process; Property; Reporting; Risk; Rupture; Severity of illness; Stroke; Systemic Lupus Erythematosus; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; TNFRSF6 gene; Techniques; Testing; Therapeutic Uses; United States; base; cardiovascular disorder risk; cohort; coronary artery calcium; cytokine; early detection biomarkers; effector T cell; experience; feeding; high dimensionality; high risk; hypercholesterolemia; improved; insight; lymph nodes; novel; novel marker; potential biomarker; single-cell RNA sequencing; stem cells; therapeutic target; tumorigenic; western diet

Abstract Cardiovascular disease (CVD) kills one in four people annually in the United States and represents a major health concern. Atherosclerosis is the main underlying trigger of CVD and is considered a chronic immune disease, in which antigen-experienced T cells accumulate within atherosclerotic plaques, leading to heart attack and stroke. While plaque destabilization is usually a slow process, diagnosing at-risk individuals often requires invasive methods; thus, there is a growing need to easily identify individuals in danger of heart attack or stroke. Mass cytometry revealed a profound loss of circulating naïve CD8 T cells (TN) in subjects with high compared to low CVD risk. Excitingly, subjects with severe CVD showed a strong increase in a CD8+ TN cell population that expressed the memory antigen CD95. Recently, a CD8+ stem cell memory T cell (TSCM) population, denoted by TN cell markers, expressing CD95, and possessing anti-tumorigenic properties, was identified in humans and mice. This CD8+ TSCM population has not been studied in the context of atherosclerosis. This proposal will test the hypothesis that this CD8+ T cell is a potential biomarker of CVD risk and is pro- atherogenic. To test this hypothesis, we will examine whether CD8+ TSCM cell frequencies are increased in the blood of severe-risk individuals within the Multi-Ethnic Study of Atherosclerosis (MESA) cohort and importantly, enhanced with myocardial infarction (MI) via conventional flow cytometry. CyTOF mass cytometry and single cell RNA sequencing (scRNA-seq) will be employed to identify novel CD8+ TSCM markers. We will also mechanistically determine whether human CD8+ TSCM cells possess a pro-atherogenic phenotype by assessing pro-inflammatory cytokine synthesis. To determine if this novel population worsens atherosclerosis, we will examine whether high fat diet feeding elicits elevated CD8+ TSCM cells within atherogenic Apolipoprotein E-/- (ApoE-/-) aorta and aorta-draining para aortic lymph nodes via flow cytometry. Adoptive transfer of CD8+ TSCM cells into immune-deficient ApoE-/- recipients will be performed to investigate whether this novel CD8+ T cell exacerbates atherosclerosis. These results will provide essential insight into how CD8+ TSCM cells contribute to atherosclerosis. Ultimately, we may unearth a novel CD8+ T cell biomarker (CD95 by TN cells) to better predict CVD-related adverse events, potentially improving diagnosis of at-risk individuals, and ultimately, ridding patients of CVD.

抽象的 心血管疾病（CVD）每年在美国杀死四分之一的人，代表 主要的健康问题。动脉粥样硬化是CVD的主要基础触发器，被认为是 慢性免疫抑制疾病，其中抗原经验的T细胞积累在动脉粥样硬化中 斑块，导致心脏病发作和中风。虽然斑块不稳定通常是一个缓慢的过程，但 诊断高危人通常需要侵入性方法。因此，越来越需要轻松 确定有心脏病或中风危险的人。质量细胞仪显示出深刻的损失 与CVD风险低相比，在较高的受试者中循环幼稚的CD8 T细胞（TN）。令人兴奋的是，主题 严重的CVD显示CD8+ TN细胞种群的强劲增加，表达了记忆 抗原CD95。最近，CD8+干细胞记忆T细胞（TSCM）种群，用TN细胞表示 表达CD95和具有抗肿瘤特性的标记物在人类和 老鼠。在动脉粥样硬化的背景下，这种CD8+ TSCM种群尚未研究。这个建议 将检验以下假设：该CD8+ T细胞是CVD风险的潜在生物标志物，并且是 动脉粥样硬化。为了检验该假设，我们将检查CD8+ TSCM细胞频率是否是 在动脉粥样硬化的多种族研究中，严重风险个体的血液增加 （MESA）队列，重要的是，通过常规流动与心肌梗塞（MI）增强 细胞仪。细胞质量细胞术和单细胞RNA测序（SCRNA-SEQ）将被聘为 识别新颖的CD8+ TSCM标记。我们还将机械确定人CD8+ TSCM是否 细胞通过评估促炎性细胞因子的合成具有促动脉粥样硬化的表型。到 确定这种新的人群是否恶化动脉粥样硬化，我们将检查高脂肪饮食是否是否 喂养引起动脉粥样硬化载脂蛋白E - / - （apoE-/ - ）主动脉和主动脉的CD8+ TSCM细胞升高 通过流式细胞仪，干扰主动脉的PARA主动脉淋巴结。 CD8+ TSCM单元的收养转移到 将执行免疫缺陷的APOE - / - 接受者，以研究这种新型CD8+ T细胞是否存在 加剧动脉粥样硬化。这些结果将提供有关CD8+ TSCM细胞的基本见解 有助于动脉粥样硬化。最终，我们可能会发掘出新的CD8+ T细胞生物标志物（TN的CD95） 细胞）更好地预测与CVD相关的不良事件，有可能改善高危的诊断。 个人，最终使CVD患者的患者。