Adipose-tissue Tregs: important players in immunological control of metabolism

在过去的三十年里，肥胖症的发病率显著上升，与此同时， 胰岛素抵抗、2型糖尿病、心血管疾病和某些癌症。肥胖和肥胖之间的关键联系 其下游合并症是由促炎性细胞因子分泌促进的慢性低度炎症， 内脏脂肪组织（VAT）中的“愤怒”脂肪细胞和巨噬细胞介导的。消炎细胞 而能够控制这些过程的分子仍然知之甚少。2009年，我们报道了一个 Foxp 3 + CD 4+调节性T细胞（TCR 4）群体，其在附睾VAT（eVAT）中高度富集，但在附睾VAT（eVAT）中不富集。 在淋巴或其他非淋巴器官中，瘦小鼠随着年龄的增长。这些细胞有一个独特的基因 表达谱、T细胞受体（TCR）库和介体依赖性谱。电子增值税 在几种胰岛素抵抗的肥胖小鼠模型中， 功能实验已经证实它们调节局部和全身炎症和代谢。一个 类似的Treg群体存在于人网膜中。eVAT T细胞作为Treg的范例 特别适合在特定组织环境中生存和发挥作用的群体。 在上一个融资周期中，我们在阐明VAT Tibet的生物学方面取得了重大进展： 转录组调节与年龄和饮食;发现一个两步，两个网站的多样化方案， 淋巴器官T细胞;揭示分子多样化的模式，包括组织的构建， Treg转录因子网络;并证明对TCR特异性、Foxp 3和IL-33的依赖性。 在这些发现的基础上，本拟议项目的总体目标是阐明新发现的 控制eVAT T细胞生成、稳态或功能的细胞和分子元件。我们 我将承担三个具体目标，每个目标都旨在解决从所获得的结果中出现的一个假设 在上一个融资周期。 1)检查脾脏PPARγlo Treg隔室的前体潜力。 2)为了确定诱发、促进或引导eVAT PPARγhi的脾PPARγlo前体的因素， 你好 3)为了确定eVAT T细胞的稳态和功能是否以及如何受到 生物钟 这些研究应该产生重要的新信息的细胞和分子途径参与 调节肥胖的毁灭性下游后果。新治疗靶点的鉴定 考虑到这些疾病令人不安的增加， 某些药物选择的不可接受的副作用。

Over the last three decades, there has been a striking rise in obesity, together with parallel increases in insulin resistance, type-2 diabetes, cardiovascular disease and certain cancers. A critical link between obesity and its downstream comorbidities is chronic low-grade inflammation promoted by secretion of pro-inflammatory mediators by “angry” adipocytes and macrophages in visceral adipose tissue (VAT). Anti-inflammatory cells and molecules capable of reining in these processes remain poorly understood. In 2009, we reported a population of Foxp3+CD4+ regulatory T cells (Tregs) that is highly enriched in epididymal VAT (eVAT), but not in lymphoid or other nonlymphoid organs, of lean mice as they age. These cells have a distinct gene- expression profile, T cell receptor (TCR) repertoire and profile of mediator dependencies. eVAT Tregs are strikingly and specifically reduced in several insulin-resistant mouse models of obesity, and loss- and gain-of- function experiments have confirmed that they regulate local and systemic inflammation and metabolism. An analogous Treg population is present in human omentum. eVAT Tregs serve as a paradigm for Treg populations specifically adapted to survive and function within particular tissue environments. Over the last funding cycle, we made substantial strides in illuminating the biology of VAT Tregs: dissecting transcriptome modulation with age and diet; discovering a two-step, two-site scenario of diversification from lymphoid-organ Tregs; uncovering modes of molecular diversification, including the construction of a tissue- Treg transcription-factor network; and demonstrating dependencies on TCR specificity, Foxp3 and IL-33. Building on these findings, the overall goal of this proposed project is to elucidate newly uncovered cellular and molecular elements controlling the generation, homeostasis or function of eVAT Tregs. We will undertake three Specific Aims, each designed to address a hypothesis that emerged from results obtained during the last funding cycle. 1) To examine the precursor potential of the splenic PPARγlo Treg compartment. 2) To identify factors that elicit, promote or guide the splenic PPARγlo precursors of eVAT PPARγhi Tregs. 3) To determine whether and how the homeostasis and function of eVAT Tregs are influenced by a circadian clock. These studies should yield important new information on cellular and molecular pathways involved in regulating the devastating downstream consequences of obesity. Identification of novel therapeutic targets within these pathways is especially important given the disconcerting increases in these disorders and the unacceptable side-effects of certain drug options.