Identification of Adipose Tissue Factors that Induce Regulatory iNKT Cells

诱导调节性 iNKT 细胞的脂肪组织因子的鉴定

• 批准号: 9537978
• 负责人: Nelson Martin LaMarche
• 金额: $ 3.73万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9537978
• 关键词: Adipocytes; Adipose tissue; Adopted; Adoptive Transfer; Animal Model; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Biological; Biology; Body Weight decreased; C57BL/6 Mouse; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chloroform; Coculture Techniques; Cytokine Signaling; Cytotoxic T-Lymphocytes; Data; Development; Diabetes Mellitus; Diet; E4BP4; Exposure to; Fatty acid glycerol esters; Genetic Transcription; Goals; Helper-Inducer T-Lymphocyte; High Pressure Liquid Chromatography; Host Defense; Human; Immune; Immune response; In Vitro; Inflammation; Interferon Type II; Interleukin-10; Interleukin-2; Interleukin-4; Laboratories; Leukocytes; Lipids; Liver; Lymphocyte; Maintenance; Major Histocompatibility Complex; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methanol; Molecular; Mus; Obesity; Organ; Pathway interactions; Phenotype; Play; Population; Production; Property; Regulatory T-Lymphocyte; Reporting; Role; Series; Signal Transduction; Spleen; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thin Layer Chromatography; Thromboplastin; Thymus Gland; Tissues; Weight Gain; Work; ZNF145 gene; alpha-galactosylceramide; cytokine; diabetes control; experimental study; in vivo; insight; insulin sensitivity; liquid chromatography mass spectrometry; macrophage; microbial; novel; prevent; programs; release factor; selective expression; solvent extraction; transcription factor

Project Summary: Invariant natural killer T (iNKT) cells are innate-like αβ T cells that use conserved T cell receptor (TCR) rearrangements to recognize lipid antigens in the context of the major histocompatibility complex (MHC) I-like molecule CD1d. Analogous to the classical Th1, Th2, and Th17 helper T cell subsets, NKT1, NKT2, and NKT17 cells have been described with stereotypical cytokine production profiles, transcription factor expression, and tissue localization. The vast majority of iNKT cells in C57BL/6 mice are NKT1 cells, which reside in the liver and spleen and produce high amounts of IFNγ and IL-4 when activated by a combination of TCR and innate cytokine signals. Many reports have described iNKT cells in the context of proinflammatory immune responses where they respond to danger signals and microbial lipid antigens to mediate host defense. In contrast, we recently identified a distinct role of iNKT cells in adipose tissues of mice and humans where they display a unique regulatory phenotype. Maintenance of the non-inflammatory state in adipose tissue is essential to preserve insulin sensitivity, prevent diabetes, and control obesity. We found that adipose iNKT cells produce high levels of IL-2 that drives the expansion of adipose Tregs and IL-10 that drives M2 macrophage expansion. These iNKT cell functions contribute significantly to the anti-inflammatory adipose microenvironment, and in the absence of iNKT cells mice are prone to obesity and diabetes. Furthermore, specific activation of adipose iNKT cells with the lipid antigen α-galactosylceramide (αGalCer) induces weight loss and ameliorates many metabolic abnormalities caused by obesity. Interestingly, adipose iNKT cells have a distinct transcriptional profile and lack expression of the PLZF transcription factor, which is expressed in iNKT cells in all other organs. Instead, they express the transcription factor E4BP4 that drives their production of IL-10. We have several lines of evidence to indicate that the regulatory properties of adipose iNKT cells are induced by exposure to the adipose microenvironment. The goal of this proposal is to identify components of adipose tissue that drive the unique regulatory phenotype of adipose iNKT cells. In line with this goal, we propose to first characterize the ability of adipose tissue to induce and maintain the regulatory iNKT cell phenotype in vivo using adoptive transfer experiments (Aim 1). Then, we will analyze the contribution of adipocyte CD1d expression to the phenotype of adipose iNKT cells (Aim 2). Finally, we will identify molecules released by adipose tissue induce E4BP4 expression in iNKT cells and endow them with regulatory capacity (Aim 3). Combined, these studies will identify environmental and molecular inducers of regulatory iNKT cells that will 1) reveal new pathways to target these cells in autoimmune diseases and 2) offer insight into the biology of an adipose-resident immune cell population that can be manipulated for the treatment of metabolic diseases such as obesity and diabetes.

项目概述：恒定自然杀伤T细胞（Invariant natural killer T，iNKT）是一种利用保守的T细胞介导的先天性αβ T细胞， 受体（TCR）重排以在主要组织相容性背景下识别脂质抗原 复合物（MHC）I样分子CD 1d。类似于经典的Th 1、Th 2和Th 17辅助性T细胞亚群， NKT 1、NKT 2和NKT 17细胞已被描述为具有典型的细胞因子产生谱， 转录因子表达和组织定位。C57 BL/6小鼠中的绝大多数iNKT细胞是 NKT 1细胞，其存在于肝脏和脾脏中，当被激活时产生大量的IFNγ和IL-4。 TCR和先天性细胞因子信号的组合。 许多报道已经描述了在促炎性免疫应答的背景下的iNKT细胞，其中 它们对危险信号和微生物脂质抗原作出反应以介导宿主防御。相比之下，我们最近 确定了iNKT细胞在小鼠和人的脂肪组织中的独特作用， 调节表型维持脂肪组织的非炎症状态对于保护 胰岛素敏感性、预防糖尿病和控制肥胖。我们发现脂肪iNKT细胞产生高水平的 驱动脂肪细胞增殖的IL-2和驱动M2巨噬细胞增殖的IL-10。这些 iNKT细胞的功能对抗炎性脂肪微环境有重要作用， 缺乏iNKT细胞的小鼠容易患肥胖症和糖尿病。此外，脂肪iNKT的特异性活化 细胞与脂质抗原α-半乳糖神经酰胺（αGalCer）诱导体重减轻，并改善许多 由肥胖引起的新陈代谢异常。有趣的是，脂肪iNKT细胞具有独特的转录调控机制， PLZF转录因子在iNKT细胞中表达，而在所有其他细胞中， 机关相反，它们表达驱动其产生IL-10的转录因子E4 BP 4。 我们有几条证据表明，脂肪iNKT细胞的调节特性是 由暴露于脂肪微环境引起。本提案的目标是确定组件 驱动脂肪iNKT细胞的独特调节表型的脂肪组织。根据这一目标， 我们建议首先描述脂肪组织诱导和维持调节性iNKT细胞的能力， 使用过继转移实验（Aim 1）在体内观察表型。然后，我们将分析 脂肪细胞CD 1d表达与脂肪iNKT细胞表型的关系（Aim 2）。最后，我们将识别分子 脂肪组织释放的E4 BP 4诱导iNKT细胞表达E4 BP 4，并赋予其调节能力 (Aim 3）。结合起来，这些研究将确定调节iNKT细胞的环境和分子诱导剂 这将1）揭示在自身免疫性疾病中靶向这些细胞的新途径， 可用于治疗代谢性疾病的脂肪驻留免疫细胞群的生物学 肥胖症和糖尿病等疾病。