Function and regulation of GATA-3

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DESCRIPTION (provided by applicant): T lymphocytes (T cells) not only play very important roles in adaptive immunity against various pathogens and malignancies but also contribute substantially to the pathogenesis of many autoimmune and allergic diseases. GATA-3 has emerged as a key transcription factor that controls the development and function of T cells. GATA-3 is not only essential for the development of the T cell lineage but also important for the production of T cell cytokines, including IL-4, IL-5, IL-13, and IL-10. In addition, studies on genetically engineered mice over-expressing GATA-3 have implied that GATA-3 may have a broader effect on T cell biology. Therefore, a better understanding of the function and regulation of GATA-3 will significantly advance our knowledge about the initiation, maintenance, and cessation of immune responses, and greatly enhance our ability to manipulate the outcomes of many infectious, malignant, inflammatory, and autoimmune diseases. However, the molecular mechanisms regulating the expression of GATA-3 are poorly understood, and studies on the function of GATA-3 are markedly hampered by the lack of live animals carrying mature GATA-3-deficient T cells. This grant application is designed to take advantage of the recently generated conditional GATA-3-deficient mice to study the regulatory role and mechanism of action of GATA-3 in later stages of T cell development (Aim 1) and in the function of various subsets of peripheral T cells (Aims 2 and 3). One attractive explanation for the broad range of function of GATA-3 in T cells is that GATA-3 is able to interact physically and functionally with various proteins. This possibility will be addressed with several in vitro approaches (Aim 4). In addition, a great effort will be dedicated to elucidating the molecular mechanisms mediating the cell type-specific expression of GATA-3 (Aim 5).