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The Transcription Factor T-bet Is Induced by Multiple Pathways and Prevents an Endogenous Th2 Cell Program during Th1 Cell Responses

ABSTRACT: T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain, in which GFP faithfully reflects the expression of T-bet. By using this tool, we report that signals elicited by IL-12 and IFNg are redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet does not contribute to its own expression when induced by IL-12 and IFNg. While both T-bet and Stat4 are critical for IFNg production, IFNg signaling is dispensable. Strikingly, loss of T-bet results in activation of an endogenous Th2 program in cells expressing T-bet-ZsGreen. Genome-wide analyses suggest T-bet directly induces Th1-related genes but indirectly suppresses Th2-related genes. Our study revealed redundancy and synergy among several Th1-inducing pathways in regulating the expression of T-bet and IFNg, and a critical role of T-bet in suppressing an endogenous Th2 program.

ORGANISM(S): Mus musculus

PROVIDER: GSE38808 | GEO | 2012/10/04

SECONDARY ACCESSION(S): PRJNA168983

REPOSITORIES: GEO

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The Transcription Factor T-bet Is Induced by Multiple Pathways and Prevents an Endogenous Th2 Cell Program during Th1 Cell Responses

Project description:T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain, in which GFP faithfully reflects the expression of T-bet. By using this tool, we report that signals elicited by IL-12 and IFNg are redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet does not contribute to its own expression when induced by IL-12 and IFNg. While both T-bet and Stat4 are critical for IFNg production, IFNg signaling is dispensable. Strikingly, loss of T-bet results in activation of an endogenous Th2 program in cells expressing T-bet-ZsGreen. Genome-wide analyses suggest T-bet directly induces Th1-related genes but indirectly suppresses Th2-related genes. Our study revealed redundancy and synergy among several Th1-inducing pathways in regulating the expression of T-bet and IFNg, and a critical role of T-bet in suppressing an endogenous Th2 program. RNA-Seq experiments were performed using total RNAs isolated from both wild type and Tbx21-/- Th1 cells in duplicates. Tbet ChIP-seq was performed using wild type Th1 cells. H3K4me1 and H3K27me3 ChIP-seq was performed using both wild type and Tbx21-/- Th1 cells.

2012-10-04 | E-GEOD-38808 | biostudies-arrayexpress

Genome-wide identification of functional elements regulated by T-bet and GATA3 in human T-cells

Project description:T-bet and GATA3 induce differentiation of CD4+ T-cells into Th1 or Th2 effectors. These exhibit a range of different properties but understanding of T-bet and GATA3 function is mostly limited to the murine Ifng and Il4/Il5/Il13 loci. We hypothesised that extending such analyses across the human genome would allow further insight into T-bet and GATA3 function. We have discovered that T-bet and GATA3 bind to multiple distal sites at a set of key immune regulatory genes. These sites display markers of functional elements, act as enhancers in reporter assays and are associated with lineage-specific expression regulated by T-bet and GATA3. Our approach also reveals that GATA3 is distributed at T-bet binding sites in Th1 cells and that T-bet directly activates its own expression. We propose that these aspects of T-bet and GATA3 function are critical for Th1/ Th2 differentiation and provide a model for the relationship between other lineage-specific regulators. ChIP was performed using antibody against T-bet in Th1 cells and against GATA3 in Th1 cells as well as Th2 cells. A sample of whole cell extract (WCE) from Th1 cells and Th2 cells was sequenced. Th1 WCE was used as the background to determine enrichment.

2012-11-16 | E-GEOD-31320 | biostudies-arrayexpress

Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation

Project description:T helper (Th) cells control host defense to pathogens. IL 12R expression is required for Th1, IL-4RM-NM-1 for Th2, and IL-6RM-NM-1/gp130 for Th17 differentiation to allow responsiveness to IL-12, IL-4, and IL-6, respectively. IL-2 via STAT5 controls Th2 differentiation by regulating the Th2 cytokine gene cluster and Il4ra expression. Here we show that IL-2 regulates Th1 differentiation, inducing STAT5-dependent IL-12RM-NM-22 and T-bet expression, with impaired human Th1 differentiation when IL-2 was blocked. Th1 differentiation was also impaired in mouse Il2-/- T cells but restored by IL-12RM-NM-22 expression. Consistent with IL-2M-bM-^@M-^Ys inhibition of Th17 differentiation, IL-2 decreased Il6ra and Il6st/gp130 expression, and Il6st augmented Th17 differentiation even when IL-2 was present. Thus, IL-2 influences T-cell differentiation by modulating cytokine receptor expression to help specify/maintain differentiated states. Genome-wide mapping of STAT1,STAT4,STAT5A,STAT5B binding to their target genes in Th1 or human CD4+ cells was conducted

2011-04-24 | E-GEOD-27158 | biostudies-arrayexpress

Cytokine receptor modulation by interleukin-2 broadly regulates T helper cell lineage differentiation

Project description:T helper (Th) cells control host defense to pathogens. IL 12R expression is required for Th1, IL-4Rα for Th2, and IL-6Rα/gp130 for Th17 differentiation to allow responsiveness to IL-12, IL-4, and IL-6, respectively. IL-2 via STAT5 controls Th2 differentiation by regulating the Th2 cytokine gene cluster and Il4ra expression. Here we show that IL-2 regulates Th1 differentiation, inducing STAT5-dependent IL-12Rβ2 and T-bet expression, with impaired human Th1 differentiation when IL-2 was blocked. Th1 differentiation was also impaired in mouse Il2-/- T cells but restored by IL-12Rβ2 expression. Consistent with IL-2’s inhibition of Th17 differentiation, IL-2 decreased Il6ra and Il6st/gp130 expression, and Il6st augmented Th17 differentiation even when IL-2 was present. Thus, IL-2 influences T-cell differentiation by modulating cytokine receptor expression to help specify/maintain differentiated states.

2011-04-24 | GSE27158 | GEO

Genome-wide identification of functional elements regulated by T-bet and GATA3 in human T-cells

2012-11-16 | GSE31320 | GEO

Methylation profiling of mouse T cells reveals epigenetic mechanisms underlie t cell plasticity

Project description:Multipotential naïve CD4+ T cells differentiate into distinct lineages including T helper 1 (Th1), Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4+ T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naïve, Th1, Th2, Th17, iTreg, and natural (n)Treg cells. We found that although modifications of signature cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, critical transcription factors such as Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and IFN-? induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4+ T helper cell differentiation. Experiment Overall Design: Different T helper subsets are profiled for mRNA expression.

2009-01-16 | E-GEOD-14308 | biostudies-arrayexpress

Comparative genomic hybridization and transcription profiling of human and mouse T cells in differentiation

Project description:ChIP-Chip for T-bet and GATA-3 in human Th1 and Th2 cells, gene expression profiling of human Th1 and Th2 cells and of T-cells from T-bet-deficient mice,

2009-10-26 | E-TABM-759 | biostudies-arrayexpress

miR-182 and miR-10a are Key Regulators of Treg specialisation and stability during Th2 and Th1-associated Inflammation

Project description:A variety of CD4+Foxp3+ Treg cell types have been described previously, indicating molecular heterogeneity within the Foxp3+ pool of CD4+ T cells. However, the factors that shape the transcriptomic identities of different Foxp3+ Treg cells are poorly understood. To identify the molecular pathways involved, we isolated CD4+Foxp3gfp+ cells from Th1-rich or Th2-rich environments following chronic Leishmania major or Schistosoma mansoni infection, respectively. Whole genome expression profiling and next generation small RNA sequencing revealed significantly different mRNA and miRNA profiles. In-silico analyses identified miR-10a and miR-182 as âregulatory miRNA hubsâ in CD4+Foxp3+ cells in Th1 and Th2-environments, respectively. Using in vitro and in vivo systems we identified that IL-12/IFNg down-regulated miR-10a and its putative transcription factor, Creb. Importantly, we demonstrated that miR-10a controls a suite of genes that regulate IFNg production in Th1-Treg cells. Also, Treg cells treated with IL-4 increased miR-182 and its putative transcription factor, cMaf. Up-regulation of miR-182 mitigated IL-2 secretion, in part through repression of IL2-promoting genes, including Bach2 and Cd2ap. This study indicates that CD4+Foxp3+ cells are influenced by their environment, and that Th1 or Th2 environments promote distinct miRNA pathways, preserving Treg stability and suppressor function. mouse infection vs. naÃ¯ve

2016-04-07 | E-GEOD-45976 | biostudies-arrayexpress

Global Mapping of Histone H3 K4 and K27 Trimethylation: Lineage Fate Determination of Differentiating CD4+ T Cells

Project description:Multipotential naïve CD4+ T cells differentiate into distinct lineages including Th1, Th2, Th17, and inducible T regulatory (iTreg) cells. The remarkable diversity of CD4+ T cells begs the question whether the observed changes reflect terminal differentiation with heritable epigenetic modifications or plasticity in T cell responses. We generated genome-wide histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) trimethylation maps in naïve, Th1, Th2, Th17, iTreg, and natural (n)Treg cells. We find that while modifications of signature cytokine genes (Ifng, Il4, and Il17) partially conform to the expectation of lineage commitment, critical transcription factors such as Tbx21 exhibit a broad spectrum of epigenetic states, consistent with our demonstration of T-bet and IFN-γ induction in nTreg cells. Our data suggest an epigenetic mechanism underlying the specificity and plasticity of effector and regulatory T cells and also provide a framework for understanding complexity of CD4+ T helper cell differentiation. genome-wide analysis of histone H3 K4 and K27 trimethylation in different sub-lineages of mouse CD4+ T cells. (12 samples in total)

2009-01-21 | E-GEOD-14254 | biostudies-arrayexpress

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

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