GATA-3 plays a central role in regulating Th1 and Th2 cell differentiation. Upon interleukin (IL)-4 binding to its receptor, GATA-3 is induced through the action of Stat6. GATA-3 regulates Th2 cytokine expression not only at the transcription level, such as directly binding to the promoters of the IL-5 and IL-13 gene, but also by the involvement in the remodeling of the chromatin structure and opening the IL-4 locus. As a master control, GATA-3 stabilizes the Th2 phenotype by two methods. First, GATA-3 shuts down Th1 development through the repression the IL-12 receptor beta2-chain expression. Second, GATA-3 augments its own expression by a positive feedback autoregulation. In this article, we review the recent study of the function of GATA-3 in Th1 and Th2 differentiation.
The development of naive CD4+ T cells into a T helper (Th) 2 subset capable of producing interleukin (IL)-4, IL-5, and IL-13 involves a signal transducer and activator of transcription (Stat)6-dependent induction of GATA-3 expression, followed by Stat6-independent GATA-3 autoactivation. The friend of GATA (FOG)-1 protein regulates GATA transcription factor activity in several stages of hematopoietic development including erythrocyte and megakaryocyte differentiation, but whether FOG-1 regulates GATA-3 in T cells is uncertain. We show that FOG-1 can repress GATA-3–dependent activation of the IL-5 promoter in T cells. Also, FOG-1 overexpression during primary activation of naive T cells inhibited Th2 development in CD4+ T cells. FOG-1 fully repressed GATA-3–dependent Th2 development and GATA-3 autoactivation, but not Stat6-dependent induction of GATA-3. FOG-1 overexpression repressed development of Th2 cells from naive T cells, but did not reverse the phenotype of fully committed Th2 cells. Thus, FOG-1 may be one factor capable of regulating the Th2 development.
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