T Lymphocyte Homeostasis in Obesity

肥胖中的 T 淋巴细胞稳态

• 批准号: 8772418
• 负责人: Karen A. Fortner
• 金额: $ 22.88万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772418
• 关键词: Adipocytes; Adipose tissue; Affect; Antigens; Autoantigens; Bromodeoxyuridine; C57BL/6 Mouse; CD44 gene; CD8B1 gene; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; Comorbidity; Data; Development; Diet; Disease; Economics; Environment; Epidemic; Fatty acid glycerol esters; Future; Genes; Goals; Health; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immunotherapy; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-10; Interleukin-15; Interleukin-7; Investigation; Knowledge; Lead; Life Expectancy; Link; Lymphoid Tissue; Measures; Mediating; Metabolic Diseases; Molecular; Mus; Obese Mice; Obesity; Output; Patients; Phenotype; Predisposition; Process; Proteins; Recruitment Activity; Regulation; Research; Risk; Role; Source; Staging; T cell response; T-Lymphocyte; TNFRSF6 gene; Testing; Therapeutic Intervention; Tumor Necrosis Factor Ligand Superfamily Member 6; Up-Regulation; Vaccination; Wild Type Mouse; Work; base; cost; cytokine; design; feeding; global health; granzyme B; improved; in vivo; insight; macrophage; mouse model; novel; novel therapeutics; prevent; public health relevance; response; treatment strategy

DESCRIPTION (provided by applicant): Obesity is a global health problem that confers a paradoxical state of both systemic inflammation and impaired immune response. The mechanisms responsible for this immune dysfunction are unclear and this gap in knowledge limits therapeutic interventions. The long-term goal of our research is to understand the molecular regulation and functional consequences of T cell homeostasis in normal development and disease states. The objective of this application is to determine how T cell homeostatic proliferation and functional capabilities are altered in obesity. Based on our preliminary findings we propose that both the reduced response to infection and the initiation of the inflammatory state in obesity result from augmented T cell homeostatic proliferation. In obesity, the expanding adipose tissue mass, combined with elevated IL-7, drive a compensatory increase in T cell homeostatic proliferation in order maintain the growing T cell compartment. Increased T cell homeostatic expansion yields T cells that could be detrimental to immune responses, as a result of their expression of inhibitory proteins (PD-1, Lag3, IL-10), and yet also contribute to chronic inflammation due to the upregulation of FasL and granzyme B. This is particularly important in adipose tissue where infiltrating CD8+ T cells have been implicated in the initiation and propagation of inflammation, yet the source and function of these CD8+ T cells has not been described. We further hypothesize that CD8+ T cells that have upregulated FasL as a consequence of homeostatic expansion stimulate Fas-expressing adipocytes to secrete proinflammatory cytokines and possibly induce adipocyte death, and thus have a pivotal role in the initiation of inflammation. These studies will advance our understanding of T cell homeostasis and function in obesity and the mechanisms that contribute to the paradox of poor immune response in the context of inflammation. These data will also provide new insight into the initiation of adipose tissue inflammation that drives many of the comorbidities seen in obese patients. This knowledge should identify potential avenues for immunotherapy to prevent inflammation and improve T cell function in obese patients that would significantly improve human health. The specific aims of this proposal are: Aim 1: Determine how T cell homeostatic proliferation and phenotype are affected by obesity. We hypothesize that T cell homeostatic proliferation, measured by in vivo BrdU incorporation, will be elevated in obese mice resulting in an increase in CD44highCD8+ T cells that express PD- 1, Lag3, and FasL. Aim 2: Determine how CD8+ T cells that have undergone homeostatic proliferation contribute to the initiation of the inflammatory cascade in adipose tissue. We hypothesize that FasL expressed by CD8+ T cells that have undergone homeostatic expansion will stimulate adipocytes to secrete inflammatory cytokines and possibly induce adipocyte death. This will be tested both in vitro and in vivo.

描述（由申请人提供）：肥胖是一个全球性的健康问题，它导致全身炎症和免疫应答受损的矛盾状态。导致这种免疫功能障碍的机制尚不清楚，这种知识上的差距限制了治疗干预。我们研究的长期目标是了解T细胞稳态在正常发育和疾病状态下的分子调控和功能后果。本申请的目的是确定T细胞稳态增殖和功能能力如何在肥胖症中改变。根据我们的初步研究结果，我们提出肥胖症对感染反应的降低和炎症状态的启动都是由于T细胞稳态增殖的增强而导致的。在肥胖症中，膨胀的脂肪组织质量与升高的IL-7结合，驱动T细胞稳态增殖的补偿性增加，以维持生长的T细胞区室。增加的T细胞稳态扩增产生可能对免疫应答有害的T细胞，这是由于它们表达抑制性蛋白（PD-1、Lag 3、IL-10），并且还由于FasL和颗粒酶B的上调而导致慢性炎症。这在脂肪组织中特别重要，其中浸润的CD 8 + T细胞已经涉及炎症的起始和传播，但这些CD 8 + T细胞的来源和功能尚未描述。我们进一步假设，由于稳态扩增而上调FasL的CD 8 + T细胞刺激表达Fas的脂肪细胞分泌促炎细胞因子并可能诱导脂肪细胞死亡，因此在炎症的起始中具有关键作用。这些研究将促进我们对肥胖症中T细胞稳态和功能的理解，以及在炎症背景下导致免疫反应低下的矛盾的机制。这些数据还将为脂肪组织炎症的启动提供新的见解，脂肪组织炎症驱动了肥胖患者中观察到的许多合并症。这些知识应该确定免疫治疗的潜在途径，以预防炎症并改善肥胖患者的T细胞功能，从而显着改善人类健康。该提案的具体目标是：目标1：确定T细胞稳态增殖和表型如何受到肥胖的影响。我们假设，T细胞稳态增殖，体内BrdU掺入测量，将在肥胖小鼠中升高，导致表达PD- 1，Lag 3和FasL的CD 44 highCD 8 + T细胞增加。目标二：确定已经经历稳态增殖的CD 8 + T细胞如何促进脂肪组织中炎症级联反应的启动。我们推测，FasL表达的CD 8 + T细胞，经历了稳态扩张将刺激脂肪细胞分泌炎性细胞因子，并可能诱导脂肪细胞死亡。这将在体外和体内进行测试。