The roles of Gata3 in controlling Treg function

描述(申请人提供)：调节性T细胞(Treg)是免疫抑制T细胞，对控制自身耐受和免疫动态平衡至关重要。完整的Foxp3功能， Foxp3是一种在Treg细胞中特异表达的X连锁转录因子，对维持Treg细胞的正常功能是必不可少的，因为Foxp3的干扰无论多么轻微，往往会导致Treg细胞功能异常，并导致炎症疾病和自身免疫的发展。调节失调的Treg细胞可能失去免疫抑制功能，并获得效应功能。因此，阐明Foxp3的表达和Treg功能是如何调控的，对于理解免疫调节和免疫耐受具有重要意义。越来越多的证据支持这样一种观点，即Treg细胞中存在通过转录因子的功能在不同类型的免疫反应过程中“感知”环境提示来调整其功能的机制。然而，我们对Treg功能的转录调控的了解还远远不完整。多年来，我们一直对识别对Treg功能重要的转录因子感兴趣。最近，我们发现GATA3在Foxp3+Treg细胞中优先表达，并且GATA3在Treg细胞中的表达可以受到细胞因子环境的调节，提示GATA3参与了Treg细胞功能的调控。GATA3是一种转录因子，最初被认为是Th2分化的主要调节因子。GATA3也是T细胞发育和NK细胞功能所必需的。因此，GATA3在控制不同类型免疫细胞的不同功能中起着关键作用。然而，GATA3是否以及如何调控Treg功能仍有待揭示。我们通过删除Foxp3+细胞中特异的GATA3基因，研究了GATA3在Treg细胞中的功能，发现Treg细胞中的GATA3缺陷导致了小鼠炎症疾病的发生。缺乏GATA3的Treg细胞表现为Foxp3表达减少、免疫抑制缺陷、外周维持受损和Th分化异常。这些结果表明，GATA3对Foxp3的表达和Treg功能是必需的。受到这些发现的启发，我们建议在此研究GATA3在Treg细胞中的这一新功能。这项拟议研究的首要目标是阐明GATA3调节Treg功能和相关免疫反应的潜在机制(S)。为了达到这一目标，具体地说，为了了解GATA3是如何通过Foxp3依赖和独立的机制，通过产生各种基因修饰的小鼠品系，并结合分子、生化和遗传学方法，实现以下研究目标：目的1.研究GATA3如何控制Foxp3的表达。目的2.探讨GATA3调控Treg动态平衡的机制。目的3.确定GATA3在调节Treg细胞Th分化中的作用。GATA3是一种转录因子，在Th2分化、T细胞发育和NK细胞功能中起关键作用。我们最近的发现揭示了GATA3在控制Treg功能中的一个新的重要作用。这项拟议的研究将揭示GATA3在Treg细胞生理、FOXP3表达和免疫调节中的基础作用机制(S)。这项研究的成功将提高人们对免疫调节的认识，加深对自身免疫和炎症性疾病病因的理解，并可能指导针对免疫性疾病的有效治疗方法的开发。

DESCRIPTION (provided by applicant): Regulatory T cells (Treg) are immune suppressive T cells that are critical to control self-tolerance and immune homeostasis. Intact function of Foxp3, an X-linked transcription factor specifically expressed in Treg cells, is essential to maintain normal function of Treg cells because perturbation of Foxp3, however slight, often leads to aberrant function of Treg cells and the development of inflammatory diseases and autoimmunity. Dysregulated Treg cells may lose immune suppressive function and also gain effector function. Therefore, elucidating how Foxp3 expression and Treg function are controlled is of great importance for the understanding of immune regulation and tolerance. Increasing evidence supports the notion that mechanisms exist in Treg cells to "sense" the environmental cues to adjust their function during different types of immune response through the functions of transcription factors. Yet, our knowledge on transcriptional control of Treg function is still far from complete. For years, we have been interested in identifying transcription factors important for Treg function. Recently, we found that Gata3 is preferentially expressed by Foxp3+ Treg cells, and that GATA3 expression in Treg cells can be modulated by cytokine milieu, suggesting that GATA3 is involved in controlling Treg cell functions. Gata3 is a transcription factor initialy identified as the master regulator for Th2 differentiation. GATA3 is also required for T cell development and NK cell function. Therefore, Gata3 plays critical roles in controlling diverse functions of different types of immune cells. Nevertheless, whether and how Gata3 regulates Treg functions remain to be revealed. We have investigated Gata3 function in Treg cells by deleting the Gata3 gene specifically in Foxp3+ cells and found that Gata3 deficiency in Treg cells led to the development of inflammatory disorders in mice. Treg cells lacking Gata3 displayed reduced Foxp3 expression, defective immune suppression, impaired peripheral maintenance and aberrant Th differentiation. These findings demonstrated that Gata3 is essential for Foxp3 expression and Treg function. Intrigued by these findings, here we propose to study this novel function of GATA3 in Treg cells. The overarching goal for this proposed study is to elucidate the underlying mechanism(s) through which Gata3 modulates Treg function and related immune response. To reach this goal, and specifically, to understand how Gata3 controls Treg function through Foxp3 dependent and independent mechanisms, by generating various genetic modified mice strains and by combining molecular, biochemical and genetic approaches, we propose to accomplish following research aims: Aim 1. Study how Gata3 controls Foxp3 expression. Aim 2. Investigate the mechanisms through which Gata3 controls Treg homeostasis. Aim 3. Determine the function of Gata3 in controlling Th differentiation of Treg cells. Gata3 is a transcription factor previously found to be critical for Th2 differentiatio, T cell development and NK cell function. Our recent findings revealed a novel essential role of GATA3 in controlling Treg function. This proposed study will uncover the mechanism(s) underlying the fundamental role of GATA3 in Treg cell physiology, Foxp3 expression and immune regulation. The success of this study will enhance the knowledge of immune regulation, will further the understanding of etiology of autoimmune and inflammatory disease, and may guide the development of effective therapies against immune diseases.