GATA3 in T cell maturation/T helper cell differentiation

描述（由申请人提供）：GATA 3，T细胞特异性转录 因子在免疫发育中起着两个核心作用。一是要 对于T淋巴谱系的发育。第二，它指导了差异化 辅助性T细胞2型淋巴细胞（Th 2细胞），并诱导产生Th 2 细胞因子，如IL-4、IL-5和IL-13。Th 2细胞介导免疫应答 过敏哮喘和寄生虫感染因为RAG嵌合体GATA 3- 缺陷小鼠在T细胞发育中有极早期的阻滞， 已知GATA 3在体内的功能。同样，GATA 3 诱导Th 2细胞因子的产生仍不清楚。我们假设1）GATA 3 在胸腺细胞发育、成熟T细胞迁移中具有重要功能， 维持Th 2表型;和2）GATA 3具有不同的结构 这些细胞因子是产生特定细胞因子所需的组分。我们 在目的1中提出产生GATA 3有条件缺陷的小鼠，例如 只有处于双阳性胸腺细胞阶段及以后的T细胞 GATA 3，和四环素应答性GATA 3表达转基因小鼠。使用 我们将在条件敲除和转基因模型中研究GATA 3的作用 在胸腺细胞发育、成熟T细胞迁移和维持Th 2 表型用其他加塔因素替代可以让我们深入了解 定义GATA 3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， GATA 3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的调查， DNA结合、蛋白质表达水平、GATA 3的乙酰化， 其他Th 2转录因子的诱导，以及尚未发现的伴侣 GATA 3在Th 2细胞因子产生机制中的作用。GATA 3基因的研究 体内和体外的研究对于治疗Th 2介导的 疾病，如过敏，哮喘，以及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.