Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses (original) (raw)
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Cutting Edge: GATA-3-Dependent Enhancer Activity in IL-4 Gene Regulation
The Journal of Immunology
Previously, we analyzed the proximal IL-4 promoter in directing Th2-specific activity. An 800-base pair proximal promoter conferred some Th2-selective expression in transgenic mice. However, this region directed extremely low reporter mRNA levels relative to endogenous IL-4 mRNA, suggesting that full gene activity requires additional enhancer elements. Here, we analyzed large genomic IL-4 regions for enhancer activity and interaction with transcription factors. The proximal IL-4 promoter is only moderately augmented by GATA-3, but certain genomic regions significantly enhanced GATA-3 promoter transactivation. Some enhancing regions contained consensus GATA sites that bound Th2-specific complexes. However, retroviral transduction of GATA-3 into developing T cells induced IL-5 to full Th2 levels, but only partially restored IL-4 production. Thus, we propose that GATA-3 is permissive, but not sufficient, for full IL-4 enhancement and may act through GATA elements surrounding the IL-13/...
Friend of GATA-1 Represses GATA-3-dependent Activity in CD4+ T Cells
Journal of Experimental Medicine, 2001
The development of naive CD4 ϩ 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 ϩ 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.
Journal of Immunology, 2001
The transcription factor GATA-3 is essential for early T cell development and differentiation of naive CD4 ؉ T cells into Th2 effector cells. To study the function of GATA-3 during T cell-mediated immune responses in vivo, we investigated CD2-GATA3transgenic mice in which GATA-3 expression is driven by the CD2 locus control region. Both in the CD4 ؉ and the CD8 ؉ T cell population the proportion of cells exhibiting a CD44 high CD45RB low CD62L low Ag-experienced phenotype was increased. In CD2-GATA3-transgenic mice, large fractions of peripheral CD4 ؉ T cells expressed the IL-1 receptor family member T1/ST2, indicative of advanced Th2 commitment. Upon in vitro T cell stimulation, the ability to produce IL-2 and IFN-␥ was decreased. Moreover, CD4 ؉ T cells manifested rapid secretion of the Th2 cytokines IL-4, IL-5, and IL-10, reminiscent of Th2 memory cells.
Journal of Biological Chemistry, 2002
Differentiation of naive CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling of Th2 cytokine gene loci. Hyperacetylation of histone H3 on nucleosomes associated with the interleukin (IL)-4, IL-13 and IL-5 genes was observed in developing Th2 cells but not in Th1 cells. Histone hyperacetylation on IL-5 gene-associated nucleosomes was Th2-specific but occurred with delayed kinetics, and hyperacetylation on RAD50 gene-associated nucleosomes was T cell antigen receptor stimulation-dependent but not Th2-specific. The induction of the Th2-specific histone hyperacetylation was STAT6-and GATA3-dependent, and interestingly, it was accompanied by the expression of intergenic transcripts within the IL-13 and IL-4 gene loci. A conserved GATA3 response element (CGRE) containing four GATA consensus sequences was identified 1.6 kbp upstream from the IL-13 gene, corresponding with the 5-border of the Th2-specific histone hyperacetylation region. The CGRE was shown to bind to GATA3, histone acetyltransferase complexes including CBP/p300, and RNA polymerase II. Also, the CGRE showed a significant enhancing effect on the Th2 cytokine gene promoters. Thus, the CGRE may play a crucial role for GATA3-mediated targeting and downstream spreading of core histone hyperacetylation within the IL-13 and IL-4 gene loci. Upon stimulation with antigens, naive CD4 T cells differentiate into two distinct T helper cell subsets, Th1 and Th2 1 (1).
Stat6Independent GATA3 Autoactivation Directs IL4Independent Th2 Development and Commitment
Immunity, 2000
we presented evidence that Th2 cells Washington University School of Medicine can develop from naive T cells independently of IL-4 St. Louis, Missouri 63110 produced by non-T cells (Schmitz et al., 1994), sug- † Deutsches Rheumaforschungszentrum gesting either that naive T cells are capable of autono-Hannoversche Strasse 27 mous IL-4 production or that non-IL-4 signals can direct 10115 Berlin Th2 development. However, a mechanistic explanation Germany for factor-independent IL-4 production by naive T cells ‡ Miltenyi Biotec was not available at that time. Friedrich-Ebert-Strasse 68 The transcription factors GATA-3 and c-Maf are selec-51429 Bergisch Gladbach tively expressed in type 2 Th cells (Ho et al., 1996; Zhang Germany et al., 1997; Zheng and Flavell, 1997). Transgenic § Department of Experimental Rheumatology GATA-3 overexpression increases Th2 cytokine produc-Charite tion, and antisense-GATA-3 blockade reduces Th2 cyto-Humboldt University kines in Th2 clones (Zheng and Flavell, 1997). GATA-3 10115 Berlin activates the IL-5 promoter (Zhang et al., 1997), and Germany GATA-3-dependent enhancer activity has been found within several regions surrounding the IL-4 gene (Ranganath et al., 1998). GATA-3 expression by retrovirus in Summary developing Th1 cells blocks IL-12 receptor expression and prevents Th1 development independently of the The initial source of IL-4-inducing Th2 development induction of IL-4 (Ouyang et al., 1998). c-Maf directly and the mechanism of stable Th2 commitment remain augments IL-4 promoter activity through cooperative obscure. We found the reduced level of IL-4 production interactions with Nip-45, NF-AT (Ho et al., 1996, 1998), in Stat6-deficient T cells to be significantly higher than and JunB (Rincon et al., 1997b). Transgenic c-Maf overin Th1 controls. Using a novel cell surface affinity maexpression increases IL-4 and alters the isotype patterns trix technique, we found that IL-4-secreting Stat6-defiof antibody with increased IgE (Ho et al., 1998), and cient T cells stably expressed GATA-3 and Th2 phenoc-Maf-deficient T cells show a selective reduction in type. Introducing GATA-3 into Stat6-deficient T cells IL-4 but not other Th2-specific cytokines (Kim et al., completely restored Th2 development, inducing c-Maf, 1999a, 1999b).