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

 描述（由申请人提供）：在过去二十年中，肥胖症显著增加，同时胰岛素抵抗、2型糖尿病和心血管疾病的发病率也平行增加。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。虽然已经鉴定和表征了脂肪组织炎症的几种正效应物，但负调节物仍然定义不清。在2009年，我们报道了一个Foxp 3 + CD 4+调节性T（Treg）细胞群体-具有独特的基因表达谱和T细胞受体库，随着年龄的增长，这些细胞在瘦小鼠的VAT中高度富集，但在淋巴组织中不富集。在几种胰岛素抵抗的肥胖小鼠模型中，这一群体明显减少。功能丧失和获得实验表明，TdR确实可以调节脂肪组织炎症，以及局部和全身代谢指标。VAT T细胞已被证明是调节性T细胞群的范例，其特别适于在特定组织部位存活和发挥功能。 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VATTreg的生物学：鉴定它们的定义转录因子，PPARs;扩展它们在控制代谢指数中的作用的证据;描绘驱动它们在衰老瘦小鼠中积累的因子，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”概念转移到骨骼肌。 基于这些发现，该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，每个目标都旨在解决上一个供资周期取得的结果中出现的一个假设。目的通过其解释特化组织Treg群体的产生的潜力而连接。我们提出：1）阐明IL-33如何驱动VAT中TdR的积累。2)确定TNF-a是否以及如何驱动肥胖小鼠中VAT TdR的损失。3)确定PPAR γ和Foxp 3如何协作以施加VAT Treg表型。 这些研究应该产生重要的新信息的分子途径参与调节肥胖的破坏性下游后果。鉴于2型糖尿病药物的一线噻唑烷二酮家族的不可接受的副作用，在这些途径中鉴定新的治疗靶点尤为重要。

 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.