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

 描述(申请人提供)：在过去的二十年里，肥胖症的发病率显著上升，同时胰岛素抵抗、2型糖尿病和心血管疾病的发病率也在增加。肥胖和下游心脏代谢紊乱之间的关键联系是慢性低度炎症，由内脏脂肪组织(VAT)中的脂肪细胞和巨噬细胞分泌促炎介质促进。虽然脂肪组织炎症的几个积极效应因素已经被识别和表征，但负面调控因素仍然没有明确的定义。2009年，我们报道了一组Foxp3+CD4+调节性T(Treg)细胞--具有独特的基因表达谱和T细胞受体谱系，随着年龄的增长，这些细胞在VAT中高度丰富，但在淋巴组织中没有。在几种胰岛素抵抗的肥胖小鼠模型中，这一群体明显减少。功能丧失和功能获得实验表明，Tregs确实可以调节脂肪组织炎症，以及局部和全身代谢指标。VAT Tregs已被证明是一种调节T细胞群体的范例，特别适应在特定组织部位的生存和功能。在上一个融资周期中，我们在以下方面取得了重大进展 阐明VAT Treg的生物学：确定它们的定义转录因子PPAR；扩展它们在控制代谢指标中的作用的证据；描述推动它们在衰老的瘦小鼠体内积累的因素，特别是Ag/MHCII和IL-1家族成员IL-33；剖析它们对肥胖的反应；以及将“组织Treg”的概念转移到骨骼肌。在这些发现的基础上，这项拟议项目的总体目标是阐明控制VAT Treg动力学的分子途径。将实现三个具体目标，每个目标都是为了解决上一个供资周期取得的成果所产生的一个假设。这些目的通过它们解释特化组织树突状细胞种群的生成的潜力而联系在一起。我们建议：1)阐明IL-33如何促进增值税中Tregs的蓄积。2)确定肿瘤坏死因子-α是否以及如何导致肥胖小鼠的VAT Tregs丢失。3)确定PPAR和FOXP3是如何协同实施增值税Treg表型的。这些研究应该会在调控肥胖的破坏性下游后果的分子途径方面产生重要的新信息。在这些途径中确定新的治疗靶点尤其重要，因为一线的噻唑烷二酮类2型糖尿病药物存在不可接受的副作用。

 DESCRIPTION (provided by applicant): There has been a striking rise in obesity over the last two decades, together with parallel increases in incidences of insulin resistance, type-2 diabetes and cardiovascular disease. A critical link between obesity and downstream cardiometabolic disorders is chronic, low-grade inflammation, promoted by secretion of pro- inflammatory mediators by adipocytes and macrophages in visceral adipose tissue (VAT). While several positive effectors of adipose-tissue inflammation have been identified and characterized, negative regulators remain poorly defined. In 2009, we reported a population of Foxp3+CD4+ regulatory T (Treg) cells - with a distinct gene-expression profile and T cell receptor repertoire that is highly enriched in the VAT, but not lymphoid tissue, of lean mice as they age. This population is strikingly and specifically reduced in several insulin-resistant mouse models of obesity. Loss- and gain-of-function experiments demonstrated that Tregs can indeed regulate adipose tissue inflammation, as well as local and systemic metabolic indices. VAT Tregs have proven to be a paradigm for regulatory T cell populations specifically adapted to survive and function at particular tissue locales. Over the last funding cycle, we made substantial strides in elucidating the biology of VAT Tregs: identifying their defining transcription factor, PPAR; extending the evidence for their role in controlling metabolic indices; delineating factors that drive their accumulation in aging lean mice, notably Ag/MHCII and the IL-1 family member, IL-33; dissecting their response to obesity; and transposing the "tissue Treg" concept to skeletal muscle. Building on these findings, the overall goal of this proposed project is to elucidate the molecular pathways that control VAT Treg dynamics. Three Specific Aims will undertaken, each designed to address a hypothesis that emerged from results obtained during the last funding cycle. The Aims are connected by their potential to explicate the generation of specialized tissular Treg populations. We propose to: 1) Elucidate how IL-33 drives accumulation of Tregs in VAT. 2) Determine whether and how TNF-a drives the loss of VAT Tregs in obese mice. 3) Determine how PPAR and Foxp3 collaborate to impose the VAT Treg phenotype. These studies should yield important new information on molecular pathways involved in regulating the devastating downstream consequences of obesity. Identification of novel therapeutic targets within these pathways is especially important given unacceptable side-effects of the front-line thiazolidinedione family of type-2 diabetes drugs.