The Role of EOS in Regulatory T-cell Biology.

EOS 在调节性 T 细胞生物学中的作用。

• 批准号: 7947180
• 负责人: DREW M. PARDOLL
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7947180
• 关键词: Ablation; Affect; Binding; C-Terminal Binding Protein 1; Cell Lineage; Cells; Cellular biology; Complex; Cues; Data; Development; Drug usage; Equilibrium; Eragrostis; Family; Gene Activation; Gene Silencing; Genes; Homeostasis; Immune; Immune response; Immunity; In Vitro; Interferons; Interleukin-17; Interleukin-2; Knock-out; Maintenance; Mediating; Mediator of activation protein; Metabolic; Methylation; MicroRNAs; Molecular; Oxidation-Reduction; Pathway interactions; Physiological; Process; RNA Interference; Regulation; Regulatory T-Lymphocyte; Role; Small Interfering RNA; Stimulus; System; T-Lymphocyte; Testing; Zinc Fingers; cytokine; flexibility; gene repression; histone modification; immune self tolerance; in vivo; mutant; promoter; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): Naturally occurring as well as adaptively developed Foxp3+CD4+ regulatory T cells (Treg) are central to the maintenance of immunological self-tolerance and immune homeostasis by suppressing aberrant or excessive immune responses. Treg specifically express the transcription factor Foxp3, which mediates the coordinate activation of genes such as CTLA-4 and GITR along with silencing of cytokines such as interleukin-2, IL-17 and interferon-?, that are normally expressed by effector T cells (Teff). The functional boundary between Treg and the Teff they are meant to suppress is not absolute. In fact, the flexibility between Treg and Teff may be an important component to both physiologic and pathophysiologic immune responses. Understanding this functional interchange requires an understanding of how immune effector genes are normally silenced in Treg. Despite progress in understanding mechanisms of Foxp3-dependent gene activation, the molecular mechanism of Foxp3-dependent gene repression has not been elucidated. Recently, we identified Eos, a zinc-finger transcription factor of the Ikaros family, as a critical mediator of Foxp3-dependent gene silencing in Treg. Eos interacts directly with Foxp3 and is necessary for gene silencing without affecting expression of Foxp3 activated genes. We further demonstrated that Eos and its corepressor C-terminal binding protein 1 (CtBP1) are necessary for histone modifications and ultimately promoter methylation involved in selective gene silencing in Treg. Knockdown of Eos in Treg abrogates their ability to suppress immune responses in vitro and in vivo. We hypothesize that Eos-CtBP-1 gene silencing is a highly regulated process in Treg that impacts on their function as suppressors vs. effectors of immunity. In the current proposal, we will further explore metabolic and microRNA dependent mechanisms of regulation of Eos-CtBP1 gene silencing in Treg as well as the in vivo consequences of ablation of this pathway for Treg development, homeostasis and modulation of adaptive immune responses. Specifically, we will 1) Elucidate the role of metabolic stimuli that affect NADH/NAD balance in Eos mediated gene silencing via the CtBP1 complex, 2) Study the regulation of Eos expression in Treg cells by microRNAs and 3) Study the consequences of Eos deletion to Treg cell homeostasis, differentiation and adaptive Treg cell development. PUBLIC HEALTH RELEVANCE: Foxp3 is a critical transcription factor that mediates both gene activation and gene repression in regulatory T cells. We have discovered a specific molecule, term Eos, that is selectively responsible for gene silencing in regulatory T cell. This proposal explore mechanism of Eos dependent Gene silencing and test the hypothesis that regulation of Eos is an important mechanism to control the regulatory T cell/ effector T cell balance in immunity.

描述（由申请人提供）：天然存在以及适应性发育的 Foxp3+CD4+ 调节性 T 细胞 (Treg) 对于通过抑制异常或过度的免疫反应来维持免疫自我耐受和免疫稳态至关重要。 Treg 特异性表达转录因子 Foxp3，它介导 CTLA-4 和 GITR 等基因的协调激活，以及通常由效应 T 细胞表达的白细胞介素 2、IL-17 和干扰素 α 等细胞因子的沉默。苔麸）。 Treg 和 Teff 之间的功能界限并不是绝对的。事实上，Treg 和 Teff 之间的灵活性可能是生理和病理生理免疫反应的重要组成部分。了解这种功能互换需要了解免疫效应基因在 Treg 中通常是如何沉默的。尽管在了解 Foxp3 依赖性基因激活机制方面取得了进展，但 Foxp3 依赖性基因抑制的分子机制尚未阐明。最近，我们发现 Eos（Ikaros 家族的锌指转录因子）是 Treg 中 Foxp3 依赖性基因沉默的关键介质。 Eos 直接与 Foxp3 相互作用，是基因沉默所必需的，而不影响 Foxp3 激活基因的表达。我们进一步证明，Eos 及其辅抑制子 C 端结合蛋白 1 (CtBP1) 对于组蛋白修饰和最终参与 Treg 选择性基因沉默的启动子甲基化是必需的。 Treg 中 Eos 的敲低会消除它们在体外和体内抑制免疫反应的能力。我们假设 Eos-CtBP-1 基因沉默是 Treg 中高度调控的过程，会影响其作为免疫抑制子与效应子的功能。在当前的提案中，我们将进一步探索调节Treg中Eos-CtBP1基因沉默的代谢和microRNA依赖性机制，以及消除该通路对Treg发育、稳态和适应性免疫反应调节的体内影响。具体来说，我们将 1) 阐明影响 NADH/NAD 平衡的代谢刺激在通过 CtBP1 复合物介导的 Eos 介导的基因沉默中的作用，2) 研究 microRNA 对 Treg 细胞中 Eos 表达的调节，以及 3) 研究 Eos 缺失的后果Treg 细胞稳态、分化和适应性 Treg 细胞发育。 公共健康相关性：Foxp3 是介导调节性 T 细胞中基因激活和基因抑制的关键转录因子。我们发现了一种特殊的分子，称为 Eos，它选择性地负责调节性 T 细胞中的基因沉默。该提案探讨了 Eos 依赖性基因沉默的机制，并检验了 Eos 调节是控制免疫中调节性 T 细胞/效应 T 细胞平衡的重要机制的假设。