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Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix]

ABSTRACT: IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions.

ORGANISM(S): Mus musculus

PROVIDER: GSE36520 | GEO | 2012/03/17

SECONDARY ACCESSION(S): PRJNA155601

REPOSITORIES: GEO

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Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Affymetrix]

Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. CD103+ Th1 and Th1 cells are profiled for mRNA expression

2012-03-17 | E-GEOD-36520 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent]

Project description:IL-4 plays an important role in the induction of Th2 and Th9 cells as well as in the inhibition of Th1 cell generation. We herein show that a combination of IL-4 and TGFbeta augment the development of Th1 cells that express CD103 (CD103+ Th1 cells) if IFNgamma is present. The T-box containing transcription factor, eomesodermin (Eomes) is preferentially expressed in CD103+ Th1 cells, and is involved in IFNgamma production. The induction of T-bet during early T cell activation is essential for the formation of the active chromatin at both the Eomes and IFNgamma gene loci. TGFbeta is required for the induction of Eomes and CD103, as well as the inhibition of Th2 cytokine expression. In addition, IL-4 induces Eomes transcription through activation of the Stat6 signaling pathway. IFNgamma-producing CD103+ Th1 cells are detected in the IEL of normal mice, and their numbers significantly decrease in Tbet- and Stat6-deficient mice. These results represent the first molecular mechanism of IL-4/TGFbeta-dependent augmentation of Th1 cell generation, and raise the possibility that IL-4 and TGFbeta may simultaneously enhance the Th1 cell-mediated immune responses under certain cytokine conditions. Th9+IFNgamma and Th9 cells are profiled for mRNA expression

2012-03-17 | E-GEOD-36554 | biostudies-arrayexpress

Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGFbeta [Agilent]

2012-03-17 | GSE36554 | GEO

Gene array for identifying molecules involved in IL-10 regulation during Th17 polarization

Project description:IL-10 production by Th17 cells is critical for limiting autoimmunity and inflammatory responses. Gene array analysis on Stat6 and T-bet double deficient Th17 cells identified the Th2 transcription factor c-Maf to be synergistically up-regulated by IL-6 plus TGFbeta, and associated with Th17 IL-10 production. Both c-Maf and IL-10 induction during Th17 polarization depended on Stat3, but not Stat6 or Stat1, and mechanistically differed from IL-10 regulation by Th2 or IL-27 signals. TGFbeta was also synergistic with IL-27 to induce c-Maf, and induced Stat1 independent IL-10 expression in contrast to IL-27 alone. Retroviral transduction of c-Maf was able to induce IL-10 expression in Stat6 deficient CD4 and CD8 T cells, and c-Maf directly transactivated IL-10 gene expression through binding to a MARE motif in the IL-10 promoter. Together, these data reveal a novel role for c-Maf in regulating T effector development, and suggest that TGFbeta may antagonize Th17 immunity by IL-10 production through c-Maf induction. Our recent studies showed that IL-6 combined with TGFbeta differed from IL-6 combined with IL-23 for IL-10 production and pathogenic activities in CD4 T cells deficient in Stat6 and T-bet, despite similar IL-17 production. We performed gene array analysis on Stat6 and T-bet double deficient cells. We rationalized that by comparing gene expression in cells treated with IL-6 plus TGFbeta versus TGFbeta alone, we would be able to identify genes specific for standard Th17 polarization, and responsible for both IL-17 and IL-10 expression. By next comparing gene expression in cells treated with IL-6 plus TGFbeta versus IL-6 plus IL-23, we could eliminate molecules involved solely in IL-17 regulation, and obtain genes specifically responsible for IL-10 regulation.

2009-03-03 | E-GEOD-15029 | biostudies-arrayexpress

Gene array for identifying molecules involved in IL-10 regulation during Th17 polarization

2009-03-03 | GSE15029 | GEO

Transcription profiling of human Th cells induced to polarize to Th1 or Th2 direction in the presence or absence of TGFbeta

Project description:Th1 and Th2 cells arise from a common precursor cell in response to triggering through the TCR and cytokine receptors for IL-12 or IL-4. This leads to activation of complex signaling pathways, which are not known in detail. Disturbances in the balance between type 1 and type 2 responses can lead to certain immune-mediated diseases. Thus, it is important to understand how Th1 and Th2 cells are generated. To clarify the mechanisms as to how IL-12 and IL-4 induce Th1 and Th2 differentiation and how TGF-beta can inhibit this process, we have used oligonucleotide arrays to examine the early polarization of Th1 and Th2 cells in the presence and absence of TGF-beta after 0, 2, 6 and 48 hours of polarization. Experiment Overall Design: This study includes altoghether 34 samples. Six different types of treatments (Thp, Th0, Th1, Th2, Th1+TGFbeta, Th2+TGFbeta) were studied at 4 time points (0, 2, 6 and 48h). There are two biological replicates, for both time series, consisting of pooled samples derived from different individuals. The early time points (0, 2 and 6h) and late time point (0 and 48h) were done in separate experiments (cell from different individuals), because of the limited number of the cells obtained from each the cord blood.

2007-12-12 | E-GEOD-2770 | biostudies-arrayexpress

Genome-wide analysis reveals unique regulation of transcription of Th2-specific genes by GATA3

Project description:Differentiation of naive CD4 T cells into type 2 helper (Th2) cells is accompanied by chromatin remodeling and increased expression of a set of Th2-specific genes including those encoding Th2 cytokines. IL-4-mediated STAT6 activation induces high levels of transcription of GATA3, a master regulator of Th2 cell differentiation, and enforced expression of GATA3 induces Th2 cytokine expression. However, it remains unclear whether the expression of other Th2-specific genes is induced directly by GATA3. A genome-wide unbiased ChIP-seq analysis revealed that GATA3 bound to 1,279 genes selectively in Th2 cells, and 101 genes in both Th1 and Th2 cells. Simultaneously, we identified 26 highly Th2-specific STAT6-dependent inducible genes by a DNA microarray analysis-based three-step selection processes, and among them 17 genes showed GATA3 binding. We assessed dependency on GATA3 for the transcription of these 26 Th2-specific genes, and 10 genes showed increased transcription in a GATA3-dependent manner while 16 genes showed no significant responses. The transcription of the 16 GATA3-nonresponding genes was clearly increased by the introduction of an active form of STAT6, STAT6VT. Therefore, although GATA3 has been recognized as a master regulator of Th2 cell differentiation, many Th2-specific genes are not regulated by GATA3 itself but in collaboration with STAT6. Th1 and Th2 subsets are profiled for mRNA expression Examination of GATA3-binding and 3 different histone modifications in Th1 and Th2 cells.

2011-03-31 | E-GEOD-28292 | biostudies-arrayexpress

Genome-wide analysis of STAT6 target genes in IL-4 treated human cord blood CD4+ cells

2010-06-25 | GSE17851 | GEO

Genome-wide analysis of STAT6 target genes in IL-4 treated human cord blood CD4+ cells

Project description:STAT6 is a major transcription factor driving the polarization of Th2 cells in response to cytokine IL-4. Here we have analyzed on a genome wide level the STAT6 mediated gene expression after IL-4 induction in naive human CD4+ T cells. RNAi mediated STAT6 knockdown was used to reveal the genes specifically regulated by STAT6. Total RNA from STAT6 siRNA treated cord blood CD4+ T cells 12, 24, 48 or 72 hours after culturing the cells in activating (antiCD3+antiCD28) plus or minus IL-4 conditions was compared to total RNA from nonspecific control siRNA treated cells. All together 18 samples were analyzed and 3 biological replicates of the culture were performed for a total of 54 samples.

2010-07-29 | E-GEOD-17851 | biostudies-arrayexpress

Genome-wide detection of STAT6 binding sites in IL-4 treated naive human CD4+ T cells

Project description:STAT6 is a major transcription factor driving the polarization of Th2 cells in response to IL-4. STAT6 is phosphorylated by Jak1 and Jak3 kinases at the IL-4 receptor, after which phosphorylated STAT6 forms a homodimer and translocates into the nucleus. There STAT6 binds to specific DNA sequences, regulating the transcription of its target genes. Here we have analyzed on a genome wide level the STAT6 binding sites, after 1h and 4h of IL-4 induction, in naive human CD4+ T cells. Keywords: SRA Altogether 5 samples from 1 biological replicate were analyzed. Activated and IL-4 treated samples were compared to only activated or untreated samples to identify unique STAT6 binding sites after IL-4 induction.

2010-06-25 | E-GEOD-17850 | biostudies-arrayexpress

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