The Role of Adipose-Resident T Cells in HIV-Associated Glucose Intolerance

脂肪驻留 T 细胞在 HIV 相关葡萄糖不耐受中的作用

• 批准号: 9429306
• 负责人: John Koethe
• 金额: $ 74.76万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9429306
• 关键词: Adipocytes; Adipose tissue; Affect; Animal Model; Antigens; Biopsy; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Density; Cells; Chronic; Cytokine Signaling; Data; Development; Diabetes Mellitus; Down-Regulation; Endocrinology; Epitopes; Fatty acid glycerol esters; Functional disorder; Future; Gene Expression; General Population; Genes; Glucose Intolerance; Goals; HIV; HIV Infections; Human; Immune; Immune system; Immunologics; Immunology; Impaired health; Impairment; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Longitudinal cohort; Macrophage Activation; Measures; Memory; Metabolic; Metabolic Diseases; National Institute of Allergy and Infectious Disease; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR gamma; Pathogenesis; Patients; Persons; Phenotype; Population; Prevalence; Process; Receptor Cell; Recruitment Activity; Research; Research Personnel; Role; Stimulus; Suction Lipectomy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; adipocyte biology; adiponectin; antiretroviral therapy; cell type; cytokine; design; diabetic; experience; glucose metabolism; immune activation; improved; insight; macrophage; memory CD4 T lymphocyte; mouse model; patient population; public health relevance; role model; success; therapeutic target; uptake; volunteer

Project Summary HIV-infected (HIV+) persons can survive decades on antiretroviral therapy, but this success is accompanied by a disproportionate burden of metabolic disease, including type 2 diabetes, in the HIV population. We hypothesize that the accumulation of chronically activated T cells in the adipose tissue of HIV+ persons is a central mechanism promoting local macrophage activation, impaired adipocyte function, and the development of HIV-associated glucose intolerance. This hypothesis is supported by our preliminary data showing 1.) a higher percentage of circulating memory CD4+ T cells in HIV+ persons is associated with insulin resistance and incident diabetes. 2.) Adipose tissue biopsies from HIV+ persons are enriched for activated CD8+ T cells compared to blood, and there is a strong correlation between the percentage of adipose-resident and circulating memory CD4+ T cells. 3.) In our murine model of obesity and insulin resistance, we found an association between adipose-resident CD8+ T cell density and T cell receptor oligoclonality, suggesting the expansion of CD8+ T cells in adipose tissue may represent an antigen-driven process Prior studies of immune activation and HIV-associated metabolic disease have only measured circulating T cell subsets. In contrast, our study will recruit a longitudinal cohort of HIV+ patients on antiretroviral therapy ranging from insulin sensitive to overtly diabetic, in addition to HIV-negative diabetic controls, to identify potential mechanistic linkages between adipose-resident T cell cytokine signaling, adipose tissue inflammation, and glucose intolerance in HIV+ persons. Our three aims will determine whether circulating blood T cell subsets are reflective of adipose-resident subsets in HIV+ persons (Aim 1), whether activated adipose-resident T cells contribute to macrophage activation, adipocyte dysfunction, and glucose intolerance (Aim 2), and whether greater adipose-resident CD8+ T cell receptor oligoclonality is correlated with metabolic dysfunction (Aim 3), which may indicate the development of HIV-associated diabetes has an antigen-driven component. This study will: 1.) clarify the role of chronic, HIV-related T cell activation in the development of glucose intolerance, 2.) assess whether the cytokine signaling profiles of adipose-resident activated, memory, and other T cell types differ from what is already known about circulating T cells, 3.) clarify the metabolic consequences of adipose tissue as a reservoir for latently HIV-infected CD4+ T cells, 4.) identify potential immunologic therapeutics targets for metabolic disease and HIV cure research, and 5.) assess whether adipose-resident CD8+ T cell oligoclonal expansion accompanies adipocyte dysfunction and glucose intolerance, and should be explored further to identify epitopes potentially contributing to HIV-associated metabolic disease. This study may also provide further insight into the role of T cells in the development of glucose intolerance in HIV-negative patients.

项目摘要 艾滋病毒感染者（HIV+）可以在抗逆转录病毒治疗中存活数十年，但这一成功是 伴随着代谢疾病的不成比例的负担，包括2型糖尿病，在艾滋病毒感染者中， 人口我们假设慢性活化的T细胞在HIV+患者的脂肪组织中的积累， 人是促进局部巨噬细胞活化、脂肪细胞功能受损和 HIV相关的葡萄糖耐受不良的发展。我们的初步数据支持这一假设 显示1.）HIV阳性者中较高比例的循环记忆CD4+ T细胞与胰岛素相关 抵抗力和糖尿病并发症。2.）的情况。来自HIV+患者的脂肪组织活组织检查富含活化的 CD8+ T细胞与血液相比，与脂肪驻留百分比之间存在很强的相关性。 和循环记忆CD4+ T细胞。3.）第三章在我们的肥胖和胰岛素抵抗的小鼠模型中，我们发现 脂肪驻留的CD8+ T细胞密度和T细胞受体寡克隆性之间的关联，表明 脂肪组织中CD8+ T细胞的扩增可能代表了一个抗原驱动的过程 先前关于免疫激活和HIV相关代谢疾病的研究仅测量了 循环T细胞亚群相比之下，我们的研究将招募一个纵向队列的HIV+患者， 抗逆转录病毒治疗范围从胰岛素敏感到明显的糖尿病，除了HIV阴性的糖尿病 对照，以确定脂肪驻留T细胞细胞因子信号传导，脂肪 组织炎症和葡萄糖耐受不良。我们的三个目标将决定 循环血T细胞亚群反映了HIV阳性者的脂肪驻留亚群（目的1）， 活化的脂肪驻留T细胞有助于巨噬细胞活化、脂肪细胞功能障碍和葡萄糖 不耐受（目的2），以及是否更大的脂肪驻留CD8+ T细胞受体寡克隆性与 代谢功能障碍（目标3），这可能表明艾滋病毒相关糖尿病的发展， 抗原驱动成分 本研究将：1.）阐明慢性HIV相关T细胞活化在葡萄糖代谢中的作用 不容忍，2.）评估脂肪驻留的细胞因子信号传导谱是否被激活，记忆， 其他T细胞类型与已知的循环T细胞不同，3。）阐明代谢 脂肪组织作为潜伏性HIV感染的CD4+ T细胞的储存库的后果，4.）识别潜在 用于代谢疾病和HIV治愈研究的免疫治疗靶点，和5.）评估是否 脂肪驻留CD8+ T细胞寡克隆扩增伴随脂肪细胞功能障碍和葡萄糖 不耐受，并应进一步探讨，以确定可能有助于艾滋病毒相关的表位 代谢性疾病这项研究也可能进一步了解T细胞在发展中的作用， HIV阴性患者的葡萄糖耐受不良。