Modifiers of Th2 development: Proteins interacting with GATA-3 and cytohesin-1

T helper cells can be classified into Th1 and Th2 subsets based on the distinct forms of cytokine production profiles. Th1 cells produce interferon gamma, interleukin-2 and tumor-necrosis factor-beta, whereas Th2 cells produce IL-4, IL-5, IL-13 and IL-6. Different Th subsets and the cytokines made by different T cell subsets play distinct roles in the clearance of pathogens and involvement of immune response. Th1 cells mediate the elimination of intracellular pathogens. IFN-γ made by Th1 subset is the major mediator of specific immune response to intracellular pathogens such as L. major and L. monocytogenes. Th2 cells mediate the clearance of large extracellular pathogens such as helminthes, acquisition of long-term immunity and involvement of allergy reactions that can cause patho-physiological outcome of asthma, and other forms of atopy. Therefore, it is of great interest to study the molecular mechanisms of T cell differentiation.; GATA-3 is the master player in Th2 development. It can not only promote Th2 cytokine gene expression, but also inhibit IFN-γ gene expression and repressing IL-12 signaling through inhibiting IL-12Rβ2 gene expression. In our study, we have shown that FOG-1, another zinc finger protein, can regulate GATA-3's function. FOG-1 can inhibit IL-5 promoter in transient transfection system. Overexpression of FOG-1 in primary T cells during early stage, but not late stage, can inhibit Th2 development. Cotransfection study showed that FOG-1 could inhibit Stat6-independent GATA-3 expression, but not Stat6-dependent GATA-3 expression. Furthermore, FOG-1−/−RAG-2−/− mouse showed defect in thymocyte development, suggesting FOG-1 is required for T cell development.; A41 is a novel identified gene that is expressed in lymphoid tissues. It is also expressed in CD3+ T cells, B220+ B cells, LAK (NK) cells, but not in bone marrow M Φ cells. It can interact with adhesion molecule cytohesin-1 in yeast two-hybrid system through its leucine rich region. Overexpression of A41 in Th2 cells and unskewed CD4 + T cells inhibits IL-4 production. A41 function analysis by utilizing RAG2 complementation showed that A41−/− ES cells have defect in B cell development from pro B cells stage to pre B cell stage, while T cell development is normal. Furthermore, A41−/− TH2 cells and A41−/− unskewed T cells make more IL-4, consistent with the result from A41 overexpression study, suggesting that A41 might downregulate IL-4 production and therefore modify Th2 development.