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）：自然发生以及自适应开发的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特异性地表达了转录因子FOXP3，该因子介导了诸如CTLA-4和GITR基因的坐标激活，以及通常由效应T细胞（TEFF）表达的细胞因子（例如interleukin-2，IL-17和干扰素）等细胞因子的沉默。 Treg和Teff之间的功能边界不是绝对的。实际上，Treg和Teff之间的柔韧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Treg中通常如何沉默的免疫效应基因。尽管在理解FOXP3依赖性基因激活的机制方面取得了进展，但尚未阐明FOXP3依赖性基因抑制的分子机制。最近，我们确定了Ikaros家族的锌指转录因子EOS，是Treg中FOXP3依赖性基因沉默的关键介体。 EOS直接与FOXP3相互作用，对于基因沉默是必要的，而不影响Foxp3激活基因的表达。我们进一步证明，EOS及其Corepressor C末端结合蛋白1（CTBP1）对于组蛋白修饰和最终参与Treg中选择性基因沉默的启动子甲基化是必需的。 Treg中EOS的敲低消除了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的一个高度调节的过程，它影响其作为抑制器与免疫效应的功能。在当前的提案中，我们将进一步探讨Treg中EOS-CTBP1基因沉默调节的代谢和依赖性机制，以及这种对Treg发育，体内稳态和适应性免疫反应调制的途径的体内后果。具体而言，我们将1）阐明通过CTBP1复合物在EOS介导的基因沉默中影响NADH/NAD平衡的作用。