GATA3 in T cell maturation/T helper cell differentiation

描述(申请人提供)：GATA3，一种T细胞特异性转录 因子在免疫发育中起着两个核心作用。首先，它是必要的 对于T淋巴系的发展。其次，它引导着差异化 T辅助2型淋巴细胞(Th2细胞)并诱导Th2的产生 细胞因子，如IL-4、IL-5和IL-13。Th2细胞介导免疫反应 过敏、哮喘和寄生虫感染。因为破布-嵌合的GATA3- 基因缺陷的小鼠在T细胞发育的早期就受到了阻碍，几乎没有 已知GATA3在体内的功能。同样，GATA3通过的机制 诱导Th2细胞因子的产生尚不清楚。我们假设GATA3 在胸腺细胞发育、成熟T细胞迁移和 保持Th2表型；2)GATA3具有明显的结构 产生特定细胞因子所需的成分。我们 在目标1中建议产生一种在GATA3中条件缺陷的小鼠，例如 只有处于双阳性胸腺细胞阶段及以上的T细胞缺乏 GATA3和四环素响应型GATA3转基因小鼠。vbl.使用 条件性基因敲除和转基因模型我们将研究GATA3的作用 胸腺细胞发育中成熟T细胞的迁移和Th2的维持 表型。与其他GATA因素的替代可以让我们深入了解 定义GATA3功能的唯一和共享域。我们有初步的 数据，使用体外和体内的替代实验，不同的 GATA3的结构域是产生IL-4、IL-5和 IL-13。在目标2中，我们描述了这些数据将如何指导我们对 DNA结合、蛋白表达水平、GATA3乙酰化的作用 诱导其他Th2转录因子，以及尚未发现的合作伙伴 GATA3在Th2细胞因子产生机制中的作用。GATA3在中国的研究 体内和体外实验对Th2介导的治疗具有重要意义 疾病，如过敏、哮喘和对寄生虫感染的反应。

DESCRIPTION (provided by applicant): GATA3, a T cell-specific transcription factor, plays two central roles in immune development. First, it is necessary for the T lymphoid lineage development. Second, it directs the differentiation of T helper type 2 lymphocytes (Th2 cells) and induces the production of Th2 cytokines, such as IL-4, IL-5 and IL-13. Th2 cells mediate the immune response in allergy, asthma, and parasitic infection. Because RAG-chimeric GATA3- deficient mice have an extremely early block in T cell development, little is known about GATA3 function in vivo. Likewise, the mechanism by which GATA3 induces Th2 cytokine production remains unclear. We hypothesize that 1) GATA3 has essential functions in thymocyte development, mature T cell migration, and maintenance of the Th2 phenotype; and 2) GATA3 has distinct structural components that are required for the production of specific cytokines. We propose in Aim 1 to generate a mouse conditionally deficient in GATA3, such that only T cells at the double positive thymocyte stage and beyond lack GATA3, and a tetracycline-responsive GATA3-expressing transgenic mouse. Using the conditional knockout and transgenic models we will study the role of GATA3 in thymocyte development, mature T cell migration and maintenance of the Th2 phenotype. Substitution with other GATA factors can give us insight into the unique and shared domains that define GATA3 function. We have preliminary data, using substitution experiments in vitro and in vivo, that distinct structural domains of GATA3 are necessary for the production of IL-4, IL-5 and IL-13. In Aim 2, we describe how these data will guide our investigation of the role of DNA binding, protein expression level, acetylation of GATA3, induction of other Th2 transcription factors, and as yet undiscovered partners of GATA3 in the mechanism of Th2 cytokine production. The study of GATA3 in vivo and in vitro has important implications for the therapy of Th2-mediated disease such as allergy, asthma, and the response to parasitic infection.