Foxo1-dependent Programme in the Control of Regulatory T Cell Function

Foxo1 依赖性程序控制调节性 T 细胞功能

• 批准号: 8960329
• 负责人: Ming Li
• 金额: $ 43.21万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-03 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960329
• 关键词: Accounting; Allergens; Antigens; Autoantigens; Autoimmune Diseases; Binding; Binding Sites; Biological Assay; Boxing; Cell physiology; Communicable Diseases; Coronavirus; Cytosol; Cytotoxic T-Lymphocyte-Associated Protein 4; DNA Binding; Defect; Diabetes Mellitus; Disease; Enhancers; FOXP3 gene; Family; Frequencies; Genes; Genetic Programming; Genetic Transcription; Graft Rejection; Health; Homeostasis; IL2RA gene; IRF1 gene; Immune; Immune Tolerance; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Interferon Type II; Interferons; Interleukin-12; Malignant Neoplasms; Maps; Mediating; Modeling; Mouse Strains; Multiple Sclerosis; Mus; Nuclear; Phosphorylation; Phosphotransferases; Play; Production; Promoter Regions; Proteins; Proteomics; Recruitment Activity; Regulation; Regulatory Element; Regulatory T-Lymphocyte; Reporter Genes; Repression; Role; STAT4 gene; Severities; Signal Pathway; Signal Transduction; Site; Staging; T cell differentiation; T-Cell Receptor; T-Lymphocyte; Tertiary Protein Structure; Testing; Toxoplasma gondii; Toxoplasmosis; base; cytokine; forkhead protein; genome-wide analysis; immunopathology; in vivo; insight; mutant; novel; oral infection; pathogen; programs; promoter; research study; restoration; transcription factor; tumor

DESCRIPTION (provided by applicant): CD4+Foxp3+ regulatory T cells (Tregs) play a pivotal role in the control of immune tolerance to self-antigens, allergens, and commensals as well as immune responses to pathogens and tumors. Our recent studies have revealed that Treg function is dependent on the transcription factor forkhead box O1 (Foxo1) mediated in part by Foxo1 suppression of the proinflammatory cytokine IFN-γ expression. In the first part of the project, we will explore the mechanisms of Foxo1-induced IFN-γ repression in Tregs. Genome-wide analysis of Foxo1 binding sites showed that Foxo1 is recruited to the regulatory elements of Ifng and Irf1, which encodes a transcription factor that promotes IFN-γ production in T cells. Foxo1 DNA binding and reporter gene assays will be performed to determine whether Foxo1 inhibits the enhancer and promoter activities of Ifng and Irf1. Proteomics studies of Foxo1-associated proteins demonstrated physical interactions between Foxo1 and the transcription factor Runx3. The precise protein domains that mediate Foxo1 interaction with Runx3 will be mapped, and their role in regulating Runx3-induced IFN-γ expression will be studied. Furthermore, the in vivo functions of IRF1, IRF1-induced IL-12Rβ1, and Runx3 in the control of IFN-γ expression and the suppressive activities of Foxo1-deficient Tregs will be determined. In the second part of the project, we will use a Toxoplasma gondii infection model to investigate whether Treg acquisition of IFN-γ expression and the associated Treg functional defects are caused by the loss of Foxo1 activities. Completion of these studies will generate mechanistic insights to the novel Foxo1-dependent genetic program that controls Treg function in the immunological steady state and during infection.

描述（由申请人提供）：CD 4 + Foxp 3+调节性T细胞（T细胞）在控制对自身抗原、过敏原和过敏原的免疫耐受以及对病原体和肿瘤的免疫应答中发挥关键作用。我们最近的研究表明Treg的功能依赖于转录因子叉头盒O 1（Foxo 1），部分由Foxo 1抑制促炎细胞因子IFN-γ表达介导。在本项目的第一部分中，我们将探讨Foxo 1诱导IFN-γ抑制TcB的机制。对Foxo 1结合位点的全基因组分析表明，Foxo 1被募集到Ifng和Irf 1的调节元件，Ifng和Irf 1编码促进T细胞中IFN-γ产生的转录因子。将进行Foxo 1 DNA结合和报告基因测定，以确定Foxo 1是否抑制Ifng和Irf 1的增强子和启动子活性。Foxo 1相关蛋白的蛋白质组学研究表明Foxo 1和转录因子Runx 3之间存在物理相互作用。 将绘制介导Foxo 1与Runx 3相互作用的精确蛋白质结构域，并研究它们在调节Runx 3诱导的IFN-γ表达中的作用。此外，还将确定IRF 1、IRF 1诱导的IL-12 R β1和Runx 3在控制IFN-γ表达中的体内功能以及Foxo 1缺陷型TcB的抑制活性。在本项目的第二部分中，我们将使用弓形虫感染模型来研究Treg获得IFN-γ表达以及相关的Treg功能缺陷是否是由Foxo 1活性丧失引起的。这些研究的完成将产生对新的Foxo 1依赖性遗传程序的机制见解，该程序在免疫稳态和感染期间控制Treg功能。