The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells

Zheng, Weiping; Flavell, Richard A.

doi:10.1016/s0092-8674(00)80240-8

Cited by 2,096 publications

(1,663 citation statements)

References 55 publications

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“…As shown in Fig. 3A, both CD4 1 T cells in spleen of WT and TRX-Tg mice contained similar frequencies of cells expressing Th1-or Th2-specific transcription factor, T-bet or GATA-3, respectively [25,26], dominantly expressed in memory (CD62L low ) fraction. Additionally, they expressed similar levels of IFN-g or IL-4 upon short-term stimulation with PMA and ionomycin with concomitant decrease in CD62L expression (Fig.…”

Section: Normal In Vitro Th2 Differentiation Of Cd4 1 T Cells From Trmentioning

confidence: 66%

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Torii

Wang

et al. 2010

Eur J Immunol

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Oxidative stress plays an important role in the pathogenesis of asthma via the upregulation of local inflammatory mediators and/or promoting Th2-skewing during Ag sensitization. Thioredoxin (TRX), a 12 kDa redox-active protein with antioxidative property, has been recently shown to play a protective role in various inflammatory diseases. Using a mouse model of asthma, we show here that IL-13 and eotaxin production are decreased in TRX-Tg mice leading to reduced eosinophils recruitment and mucus metaplasia. The reduction in airway inflammation occurs without the attenuation of systemic Th2 immunity in that comparable levels of Th2-type cytokines and Ig were detected in LN and serum, respectively, from TRX-Tg and WT mice. Likewise, CD4 1 T cells from both strains of mice developed similar Th1 and Th2 responses in vitro. Asthmatic lungs of TRX-Tg and WT mice contained similar amounts of GATA-3 1 and Foxp3 1 T cells. Finally, production of MIF, an upstream modulator of airway inflammation, was significantly reduced in the lungs of TRX-Tg mice. Our data suggest that TRX suppresses airway inflammation by inhibiting MIF production thereby limiting the downstream recruitment of eosinophils to the lung independently of modulating systemic Th1/Th2 immunity.

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Section: Normal In Vitro Th2 Differentiation Of Cd4 1 T Cells From Trmentioning

confidence: 66%

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Torii

Wang

et al. 2010

Eur J Immunol

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“…17,18,21,32,33 Other helper T-cell phenotypes are regulated in similar ways, such as the Treg phenotype and its master transcription factor FOXP3 19 and the cytokine TGFb, or the Th17 phenotype governed by RORgt and IL17, 34,35 but as of yet little is known about their epigenetic regulatory mechanisms.…”

Section: The Modelmentioning

confidence: 99%

“…Gene expression is regulated by so-called master regulators, which are self-activating transcription factors that are both necessary and sufficient for the induction of a particular phenotype. [17][18][19] A range of chromatin modifications, such as histone modification by methylation or acelylation, and DNA modification by CpG methylation, allow helper T-cell phenotypes to become heritable by epigenetic imprinting, and thus foster the formation of cells resembling their original phenotype. 20 Cytokine loci, which tend to be repressed in naive T cells, are derepressed when the T cell adopts a particular phenotype.…”

mentioning

confidence: 99%

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Ham

Boer

2012

Immunol Cell Biol

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Following activation by antigen, helper T cells differentiate into one of many effector phenotypes. Formulating mechanistic mathematical models combining regulatory networks at the transcriptional, translational and epigenetic level, we study how individual helper T cells may adopt their different phenotypes. For each cytokine phenotype, for example, T helper type 1 (Th1) and type 2 (Th2) cells, we find that the intracellular molecular network allows a cell to adopt one of the three states, which we interpret as naive, active and memory states. Cell division markedly speeds up the differentiation into a particular memory state because of DNA demythelation. In a memory state, cells readily resume production of the same cytokine they produced before. Using stochastic models we show that helper T-cell plasticity (that is, the ability to switch phenotype) is low during clonal expansion. Although most memory cells rapidly secrete the original cytokine upon restimulation, some adopt another phenotype and produce different cytokines, allowing for considerable diversity in the phenotypes that are adopted during a memory response. In summary, we show that helper T-cell division expedites cell differentiation by increasing DNA demethylation. We also show that plasticity is low during the clonal expansion phase, but that helper T cells may adopt alternative phenotypes during a memory response. Keywords: epigenetic regulation; helper T-cell phenotypes; mathematical modelling; transcriptional regulation For more than a century, biologists have studied the mechanisms that enable cells to encode genetic information, and how this information is passed on to the cell's progeny. 1 Besides the genetic DNA code of a cell that is replicated faithfully upon every cell division and therefore virtually identical in every cell within an individual, 2 additional 'epigenetic' information fixes differential cell development by prompting daughter cells to express a similar set of genes as their mother cell. 3 This facilitates and thus preserves the differentiation process that the mother cell and its ancestors have undergone as part of cellular diversification within an organism.A variety of biological systems have now been studied using highthroughput technologies, which provide data that allow a better understanding of information processing within a cell. [4][5][6][7] The availability of quantitative data and the apparent complexity of cellular regulatory networks have led to a data-driven mathematical modelling approach that is usually referred to as computational or systems biology. Mathematical models have revealed nonlinearity in genetic networks that allow cells to switch between states. Examples are the Lac operon 8 and cells of the haematopoietic lineage. [9][10][11][12] Recently, epigenetic regulation mediated by histone modification has been studied using similar mathematical models. [13][14][15] At the molecular level these mathematical models describe quite different genetic and epigenetic systems. Mathematically they share im...

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“…Activation of uncommitted CD4 T cells results in low level transcription of both Th1 and Th2 cytokine loci [8,9] and upstream regulators [10]. Under the influence of STAT (signal transducer and activation of transcription) signaling, the expression of signature cytokines such as IFN-c and IL-4 and the upstream transcription factors Tbet, GATA-3 and c-maf becomes restricted to distinct Th1-or Th2-specific programs [7][8][9][10][11][12][13]. Once established, the chosen patterns are retained as heritable traits, which are stable to changes in the cytokine milieu [14] and STAT activity [15].…”

Section: Introductionmentioning

confidence: 99%

Nuclear repositioning marks the selective exclusion of lineage‐inappropriate transcription factor loci during T helper cell differentiation

et al. 2004

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To address how heritable patterns of gene expression are acquired during the differentiation of Th1 and Th2 cells, we analyzed the nuclear position of lineage-restricted cytokine genes and their upstream regulators by 3-dimensional fluorescence in situ hybridization. During Th1 differentiation, GATA-3 and c-maf loci, which encode upstream regulators of Th2 cytokines, were progressively repositioned to centromeric heterochromatin as defined by a c-satellite repeat probe and/or the nuclear periphery, compartments that have been associated with transcriptional repression. A third transcription factor locus, T-bet, which controls Th1-specific programs, was subject to de novo CpG methylation in a Th2 cell clone. In contrast, we did not find repositioning of the cytokine gene loci IL-2, IL-3, IL-4 or IFN-c during T helper cell differentiation. Instead, IFN-c was constitutively associated with the nuclear periphery, even when primed for expression in Th1 cells. Our results suggest that Th1/Th2 lineage commitment and differentiation involve repositioning of the regulators of cytokine expression, rather than the cytokine genes themselves.

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The Transcription Factor GATA-3 Is Necessary and Sufficient for Th2 Cytokine Gene Expression in CD4 T Cells

Cited by 2,096 publications

References 55 publications

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

Cell division curtails helper phenotype plasticity and expedites helper T‐cell differentiation

Nuclear repositioning marks the selective exclusion of lineage‐inappropriate transcription factor loci during T helper cell differentiation

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