Protein Kinase A Regulates GATA-3-Dependent Activation of IL-5 Gene Expression in Th2 Cells (original) (raw)
Related papers
Stat6-Independent GATA-3 Autoactivation Directs IL-4-Independent Th2 Development and Commitment
Immunity, 2000
1997). Previously, 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). Th2-specific DNase I hypersensitive sites in the IL-4 While these studies have added to our understanding locus, and Th2 cytokine expression. The fact that of cytokine gene regulation, much less is known about GATA-3 fully reconstitutes Th2 development in Stat6how GATA-3 and c-Maf expression themselves are regudeficient T cells indicates it is a master switch in Th2 lated. In naive T cells, these factors are expressed at development. Finally, GATA-3 exerts Stat6-indepenlow levels, which increase over the first week of Th2 dent autoactivation, creating a feedback pathway stadevelopment (Ho et al., 1996; Zhang et al., 1997; Zheng bilizing Th2 commitment. and Flavell, 1997; Ouyang et al., 1998). The pathways and controlling elements directing their Th2-specific
In vivo studies fail to reveal a role for IL4 or STAT6 signaling in Th2 lymphocyte differentiation
Proceedings of The National Academy of Sciences, 2008
The expression of interleukin-4 (IL-4) is viewed as the hallmark of a Th2 lymphocyte, whereas the subsequent action of IL-4 and IL-13, mediated through the STAT6 signaling pathway, is seen as a prerequisite for the full development of Th2 immune responses to parasites and allergens. G4 mice, whose IL-4 gene locus contains the fluorescent reporter eGFP, were used to quantify the number of Th2 cells that develop during Nippostrongylus brasiliensis-or allergen-induced immune responses under conditions where IL-4 or STAT6 was absent. Here, we show that deletion of IL-4 or STAT6 had little impact on the number or timing of appearance of IL-4-producing Th2 cells. These data indicate that in vivo differentiation of naïve CD4 T cells to Th2 status often occurs independently of IL-4 and STAT6 and that recently described pathways of Th2 cell differentiation may explain how allergens and parasites selectively induce Th2-mediated immunity.
Cell Regulation, 1990
Activation of T cells results in the production of lymphokines and cellular proliferation. Protein kinase C (PKC) plays a key role in this process. It has been shown that this enzyme is essential to elicit a response to Con A or specific antigen in CD4+ T helper type 1 (Th 1) cells that secrete IL-2. We have now explored the signal transduction pathway that leads to transcription of the IL-4 gene and proliferation in murine CD4+ T helper type 2 (Th 2) cells. Surprisingly, we have found in two independently derived Th 2 clones that neither cellular proliferation nor IL-4 lymphokine production is affected by blocking or depletion of PKC. This differential mechanism of signal transmission leading to cellular activation implies a new distinction between murine Th 1 and Th 2 cells.
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.