Regulation and Maintenance of Adipose Tissue T cells

摘要 脂肪组织(AT)是一种活跃的新陈代谢器官，它包含一个免疫细胞网络，其相互干扰 调节脂肪组织动态平衡。作为对肥胖的反应，这些免疫细胞可以被激活， 扩张并分泌脂肪因子和促炎细胞因子，以修饰局部和全身的胰岛素 敏感性，并有助于代谢功能障碍和2型糖尿病的发展。促销和 肥胖状态下脂肪组织炎症的维持已被证明涉及激活 脂肪组织T细胞(ATT)，增强促炎脂肪组织巨噬细胞的活性 (自动取款机)在肥胖小鼠模型上。我们对这些机制的理解存在着根本性的差距 维持哪些ATT，它们相对于其他T细胞亚群的多样性，以及ATT对哪些信号 在脂肪组织重塑和扩张过程中做出反应。我们评估早期ATT动力学的初步数据 证明ATT的增殖是对短期高脂饮食引起的AT快速扩张的反应 (HFD)喂食。在这些实验中评估的时间点在PRO-2的大量渗透之前 与肥胖状态相关的炎症性ATM，提示ATT在AT的启动中起重要作用 在肥胖状态下观察到的炎症。这一提议试图检验ATT在 对短期HFD喂养的反应需要来自抗原提呈细胞(APC)的信号。此外， 提出的研究将询问记忆ATT的建立以及驱动记忆ATT的决定因素 启动他们对肥胖状态下AT变化的反应。最后，私家侦探之前的研究发现了一个独特的 TCRCD3+αβ-CD8-双阴性(DN)ATT的群体，并将检验以下假设 具有维持AT动态平衡和调控效应器的免疫调节表型和功能 ATTS在肥胖发展过程中的作用。为了验证这些假设，拟议的项目将进行以下工作 本奖项K99阶段的目标：1)确定短期HFD期间ATT增殖的驱动因素(S) 2)确定瘦肉型和肥胖型糖尿病肾病ATT的表型和功能。在此期间， PI将接受关于小鼠营养新陈代谢、生物信息学和序列分析的研究培训，以及 肥胖症和糖尿病的翻译研究。在独立的R00阶段，PI将继续这些 目的并寻求3)确定驻留记忆ATT的建立以及它们诱导所需的信号 和维护。这项工作的完成将对确定ATT的监管机构产生重大影响 瘦身和肥胖状态的功能和阐明抑制肥胖相关的AT炎症的新靶点 由ATT反应调节。在K99阶段中概述的拟议技术培训将确保成功 形成了以肥胖相关炎症和肥胖为中心的独立研究计划 代谢功能障碍以及ATT如何在AT的启动、协调和维持中起作用 炎症和随后的胰岛素抵抗。

ABSTRACT Adipose tissue (AT) is an active metabolic organ that contains a network of immune cells whose crosstalk regulates adipose tissue homeostasis. In response to obesity, these immune cells can become activated, expand, and secrete adipokines and pro-inflammatory cytokines that modify local and systemic insulin sensitivity and contribute to the development of metabolic dysfunction and type 2 diabetes. Promotion and maintenance of adipose tissue inflammation in the obese state has been shown to involve the activation of adipose tissue T cells (ATT), which potentiate the activity of pro-inflammatory adipose tissue macrophages (ATMs) in mouse models of obesity. There is a fundamental gap in our understanding of the mechanisms by which ATTs are maintained, their diversity relative to other T cell subsets, and the signals to which ATTs respond during adipose tissue remodeling and expansion. Our preliminary data assessing early ATT kinetics demonstrated that ATTs proliferate in response to the rapid AT expansion induced by short-term high-fat diet (HFD) feeding. Timepoints assessed in these experiments precede the substantial infiltration of pro- inflammatory ATMs associated with the obese state, suggesting ATTs play vital roles in the initiation of AT inflammation observed in the obese state. This proposal seeks to test the hypothesis that ATT proliferation in response to short-term HFD feeding requires signals from antigen presenting cells (APCs). Further, the proposed research will interrogate the establishment of memory ATT and the determinant which drive the priming of their responses to AT changes in the obese state. Lastly, the PI’s prior research uncovered a unique population of TCRαβ CD3+ CD4- CD8- double negative (DN) ATTs and will test the hypothesis that DN ATTs possess an immunoregulatory phenotype and function in maintaining AT homeostasis and controlling effector ATTs during development of obesity. To test these hypotheses, the proposed project will pursue the following Aims during the K99 phase of this award: 1) To determine driver(s) of ATT proliferation during short-term HFD feeding and 2) to identify phenotype and function of DN ATTs in the lean and obese state. During this time, the PI will receive research training in nutrient metabolism in mice, bioinformatics and sequencing analysis, and translational research in obesity and diabetes. During the independent R00 phase, the PI will continue these Aims and seek to 3) determine establishment of resident memory ATTs and signals required for their induction and maintenance. Completion of this work will have significant impact on identification of the regulators of ATT functions in lean and obese states and elucidate novel targets to suppress obesity-associated AT inflammation mediated by ATT responses. Training in proposed techniques outlined in the K99 phase will ensure successful formation of the PI’s independent research program centering on obesity-associated inflammation and metabolic dysfunction, and how ATTs contribute to the initiation, orchestration, and maintenance of AT inflammation and subsequent insulin resistance.