GATA3 in T cell maturation/T helper cell differentiation

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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.