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The Role of EOS in Regulatory T-cell Biology.

EOS 在调节性 T 细胞生物学中的作用。

基本信息

批准号：
8683077
负责人：
DREW M. PARDOLL
金额：
$ 40.59万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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.

描述（由申请人提供）：天然存在的以及适应性发育的Foxp 3 + CD 4+调节性T细胞（Treg）通过抑制异常或过度的免疫应答，对维持免疫自身耐受性和免疫稳态至关重要。Treg特异性表达转录因子Foxp 3，其介导CTLA-4和GITR等基因的协同激活，同时沿着细胞因子如白细胞介素-2、IL-17和干扰素-β的沉默，通常由效应T细胞（Teff）表达。Treg和Teff之间的功能边界不是绝对的。事实上，Treg和Teff之间的灵活性可能是生理和病理生理免疫应答的重要组成部分。理解这种功能互换需要理解免疫效应基因通常如何在Treg中沉默。尽管在理解Foxp 3依赖性基因激活的机制方面取得了进展，但Foxp 3依赖性基因抑制的分子机制尚未阐明。最近，我们确定了Eos，Ikaros家族的锌指转录因子，作为Treg中Foxp 3依赖性基因沉默的关键介质。Eos直接与Foxp 3相互作用，是基因沉默所必需的，而不影响Foxp 3激活基因的表达。我们进一步证明，Eos及其辅阻遏物C-末端结合蛋白1（CtBP 1）是必要的组蛋白修饰，并最终启动子甲基化参与选择性基因沉默在Treg。Treg中Eos的敲低消除了它们在体外和体内抑制免疫应答的能力。我们假设Eos-CtBP-1基因沉默是Treg中一个高度调节的过程，影响其作为免疫抑制因子与效应因子的功能。在目前的提案中，我们将进一步探索调节Treg中Eos-CtBP 1基因沉默的代谢和microRNA依赖性机制，以及消融该通路对Treg发育、稳态和适应性免疫应答调节的体内后果。具体而言，我们将1）阐明影响NADH/NAD平衡的代谢刺激在Eos介导的基因沉默中通过CtBP 1复合物的作用，2）研究Eos在Treg细胞中的表达通过microRNA的调节和3）研究Eos缺失对Treg细胞稳态，分化和适应性Treg细胞发育的后果。