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

脂肪组织 Tregs：代谢免疫控制的重要参与者

基本信息

批准号：
10585127
负责人：
DIANE J MATHIS
金额：
$ 42.38万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-12 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10585127
关键词：
Ablation Address Adipocytes Adipose tissue Age Aging Autoimmunity Biological Assay Cardiovascular Diseases Cell Compartmentation Cells Collaborations Communication Data Dependence Deposition Explosion FOXP3 gene Female Fibrosis Genetic Transcription Goals Growth Health Homeostasis Human Hypersensitivity Immune response Immunologics In Vitro Inflammation Literature Malignant Neoplasms Mediator Metabolic Metabolic Diseases Metabolic dysfunction Metabolism Microbe Molecular Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Obesity PPAR gamma Phenotype Population Poverty Process Production Regulatory T-Lymphocyte Reporting Rodent T-cell receptor repertoire Testing Thinness Tissues Visceral adipocyte differentiation age effect age related comorbidity dimorphism experimental group head-to-head comparison in vivo in vivo evaluation insulin sensitivity insulin sensitizing drugs lipid biosynthesis lymphoid organ male mesenchymal stromal cell novel oncostatin M precursor cell programs receptor response sex sexual dimorphism side effect stem cells transcriptome transcriptomics tumor

项目摘要

Foxp3+CD4+ regulatory T cells (Tregs) control most types of immune responses. Recently, distinct compartments of tissue-localized Tregs that help maintain local homeostasis were also discovered. These so- called “tissue-Tregs” have transcriptomes, TCR repertoires and growth/survival factor dependencies that differ from those of lymphoid-organ Tregs and of Tregs in other tissues. Tissue-Tregs regulate non-immunological processes such as metabolism and regeneration via influences on innate and adaptive immunocytes as well as on local stromal and parenchymal cells. A paradigmatic tissue-Treg compartment, first reported by the PI's lab in 2009, is that found in visceral adipose tissue (VAT), especially the epidydimal VAT (eVAT) depot of lean mice. eVAT Tregs, which depend on the supreme regulator of adipogenesis, PPARγ, for effective accrual and function, help assure local and systemic metabolism, notably insulin sensitivity. This important function is known to reflect direct eVAT-Treg influences on local immunocytes and on eVAT-resident, immunocyte-promoting mesenchymal stromal cells (VmSCs). The focus of this proposed project is on a newly discovered function of eVAT Tregs. Our preliminary data, primarily derived from transcriptomic analyses and in vitro adipogenesis assays, indicate that they control the differentiation of stroma-resident adipocyte precursor cells into mature adipocytes (and potentially adipocyte turnover and fibrosis). Moreover, these data point to Oncostatin M (OSM) as a potential mediator of these influences. THE MAJOR GOAL OF THIS PROPOSED PROJECT IS TO ELUCIDATE THE AVENUES OF COMMUNICATION BETWEEN eVAT Tregs AND ADIPOCYTE PRECURSORS. We propose: (1) To determine the extent to which OSM production by eVAT-Tregs is responsible for their constraint of stroma- resident adipocyte precursors. This Aim addresses the need to validate our transcriptomic and in vitro adipogenesis data with in vivo examinations. (2) To evaluate the effects of aging on eVAT-Treg control of local inflammation and adipogenesis. Discrepancies in the literature imply that the impact of eVAT Tregs may be very different in aging vs old mice. We propose to evaluate this notion in a head-to-head comparison of mice specifically lacking eVAT-Tregs or not. (3) To determine whether and how eVAT-Treg control of adipocyte differentiation shows sexual dimorphism. Male and female rodents and humans differ in the deposition and function of their adipose tissue. A recent report (on which the PI's lab collaborated) highlights a male:female dichotomy in IL-33-producing, immunocyte- promoting VmSCs, leading to a dimorphism in gonadal VAT accrual. Our preliminary data uncovered a difference in adipocyte dynamics as well, which is the focus of this Aim. Upon successful completion of this proposed project, we should know in what contexts eVAT-Tregs regulate adipocyte dynamics and how they do so. This represents a novel function of eVAT Tregs, one that fits within the emerging theme of tissue-Treg control of stem/progenitor cell activities.

Foxp3+CD4+ 调节性 T 细胞 (Treg) 控制着大多数类型的免疫反应。还发现了有助于维持局部稳态的组织局部调节性T细胞的区室。被称为“组织调节性T细胞”的转录组、TCR库和生长/存活因子依赖性各不相同不同于淋巴器官 Tregs 和其他组织中的 Tregs 调节非免疫功能。通过影响先天性和适应性免疫细胞以及 PI 实验室首次报道了典型的组织 Treg 区室。 2009年，在内脏脂肪组织（VAT）中发现了这种物质，尤其是瘦小鼠的附睾脂肪组织（eVAT）。 eVAT Tregs 依赖于脂肪生成的最高调节因子 PPARγ，以实现有效的增长和功能，有助于保证局部和全身的新陈代谢，显着的胰岛素敏感性反映了这一重要功能。 eVAT-Treg 对局部免疫细胞和 eVAT 驻留、免疫细胞促进间充质细胞的直接影响该项目的重点是我们新发现的 eVAT Tregs 功能。主要来自转录组分析和体外脂肪生成测定的初步数据表明它们控制基质驻留脂肪细胞前体细胞分化为成熟脂肪细胞（和此外，这些数据表明制瘤素 M (OSM) 是一种潜在的该项目的主要目标是阐明这些影响的中介者。 eVAT Tregs 和脂肪细胞前体之间的沟通途径。 (1) 确定 eVAT-Tregs 产生的 OSM 在多大程度上对其基质的限制负责该目标解决了验证我们的转录组学和体外研究的需要。体内检查的脂肪生成数据。 (2) 评估衰老对 eVAT-Treg 控制局部炎症和脂肪生成差异的影响。文献中暗示 eVAT Tregs 对衰老小鼠和老年小鼠的影响可能非常不同。通过对是否特别缺乏 eVAT-Treg 的小鼠进行头对头比较来评估这一概念。 (3)确定eVAT-Treg对脂肪细胞分化的控制是否以及如何表现出性别二态性。雄性和雌性啮齿动物以及人类的脂肪组织沉积和功能不同。（PI 实验室合作）强调了 IL-33 产生、免疫细胞中的男性和女性二分法促进 VmSC，导致性腺增值税应计的二态性我们的初步数据发现了差异。脂肪细胞动力学也是如此，这是该目标的重点。成功完成该拟议项目后，我们应该知道 eVAT-Tregs 在哪些情况下进行监管脂肪细胞动力学及其如何发挥作用，这代表了 eVAT Tregs 的一项新功能，它符合脂肪细胞的功能。组织 Treg 控制干细胞/祖细胞活动的新兴主题。