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.

摘要 心血管疾病（CVD）每年在美国杀死四分之一的人， 主要的健康问题。动脉粥样硬化是心血管疾病的主要潜在触发因素， 慢性免疫性疾病，其中抗原经历的T细胞在动脉粥样硬化内积聚 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， 诊断高危个体通常需要侵入性方法;因此，越来越需要容易地 识别有心脏病发作或中风危险的个体。质谱分析显示， 在高CVD风险与低CVD风险受试者中的循环幼稚CD 8 T细胞（TN）。令人兴奋的是， 严重CVD患者的CD 8 + TN细胞群表现出强烈的增加， CD 95抗原。最近，CD 8+干细胞记忆T细胞（TSCM）群体，表示为TN细胞， 在人类中鉴定了表达CD 95并具有抗肿瘤特性的标记物， 小鼠尚未在动脉粥样硬化的背景下对该CD 8 + TSCM人群进行研究。这项建议 将检验这一假设，即这种CD 8 + T细胞是CVD风险的潜在生物标志物， 致动脉粥样硬化的为了验证这一假设，我们将检查CD 8 + TSCM细胞频率是否与 在动脉粥样硬化的多种族研究中， （梅萨）队列，重要的是，通过常规血流增强心肌梗死（MI） 细胞仪将采用CyTOF质谱细胞术和单细胞RNA测序（scRNA-seq）来 鉴定新的CD 8 + TSCM标志物。我们还将机械地确定人CD 8 + TSCM是否 通过评估促炎细胞因子合成，细胞具有促动脉粥样硬化表型。到 为了确定这个新的人群是否患有动脉粥样硬化，我们将检查高脂肪饮食是否 在致动脉粥样硬化的载脂蛋白E-/-（ApoE-/-）主动脉内喂养elvinated升高的CD 8 + TSCM细胞， 经流式细胞术检测主动脉旁淋巴结引流。将CD 8 + TSCM细胞连续转移到 免疫缺陷型ApoE-/-受体将进行研究，以研究这种新的CD 8 + T细胞是否 加重动脉粥样硬化。这些结果将为CD 8 + TSCM细胞 导致动脉粥样硬化。最终，我们可能会发现一种新的CD 8 + T细胞生物标志物（CD 95，TN 细胞），以更好地预测心血管疾病相关的不良事件，潜在地提高诊断的风险 个体，并最终摆脱CVD患者。