REGULATION OF TH2 DIFFERENTIATION AND<i>Il4</i>LOCUS ACCESSIBILITY

Ansel, K. Mark; Djuretic, Ivana; Tanasă, Bogdan; Rao, Anjana

doi:10.1146/annurev.immunol.23.021704.115821

Cited by 589 publications

(580 citation statements)

References 259 publications

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“…5,19 Jurkat cells were used here in expression studies to establish Th lineage conditions as shown previously. [20][21][22] Th2-like expression profiles were induced by addition of hrIL4 and a-INFg to the cell culture and Th1-like conditions by tumor necrosis factora addition, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Among others, interleukin 4 (IL4) acts as a regulator to counter-play the inflammatory immune processes. 4 Usually, IL4 is secreted by lymphocytes of the Th2 lineage, 5 whereas the IL4 locus appears silenced in Th1 cells. Because of its immune response regulating role, IL4 is an obvious candidate gene for potential association in MS. We focus here on the IL4 promoter polymorphism À589C/T, since numerous studies have shown association of this single nucleotide polymorphism (SNP) with various inflammatory diseases, including asthma, atopy, brucellosis and rheumatoid arthritis, [6][7][8][9][10][11] and because earlier deletion expression assays hinted to a functional role of this SNP.…”

Section: Introductionmentioning

confidence: 99%

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Sex specifically associated promoter polymorphism in multiple sclerosis affects interleukin 4 expression levels

et al. 2007

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The interleukin 4 promoter polymorphism À589 C/T (rs2243250) was genotyped in 869 multiple sclerosis (MS) patients and 595 healthy blood donors. Sex-specific MS association was evident whereas two flanking polymorphisms showed insignificant P values. In dual luciferase assays of cultured Jurkat cells the cloned promoter comprising the À589 T allele leads to higher expression as compared to the respective construct with the C allele. Together these findings may be discussed functionally as contributing to the genetic predisposition and to the pathogenesis in MS.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sex specifically associated promoter polymorphism in multiple sclerosis affects interleukin 4 expression levels

et al. 2007

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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%

“…The type of epigenetic modification that we model is CpG methylation, as this is one of the principle mechanisms of heritable epigenetic modification. 32 DNA methylation after cell division in mammals is primarily mediated by DNA methyltransferases (DNMTs) that remethylate the new hemimethylated DNA strand. Upon cell division, DNMT1 preferentially associates with the new strand to methylate it.…”

Section: Box 1 Positive Feedback Creates Attractorsmentioning

confidence: 99%

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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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GATA-3 up-regulation in CD8+ T cells as a biomarker of immune dysfunction in systemic sclerosis, resulting in excessive interleukin-13 production

Medsger¹,

Ivanco²,

Kardava³

et al. 2011

Arthritis & Rheumatism

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Objective. Despite the importance of interleukin-13 (IL-13) in systemic sclerosis (SSc) and other fibrotic diseases, its mechanisms of action are not understood. We have reported that excessive amounts of IL-13 are produced by peripheral blood effector CD8؉ T cells from patients with diffuse cutaneous SSc (dcSSc). The aim of the present study was to establish the molecular basis of IL-13 dysregulation in the pathogenesis of SSc.Methods. Quantitative polymerase chain reaction analysis and intracellular staining were used to study the transcription factors that control naive peripheral blood CD8؉ T cell differentiation into type 1 and type 2 cytokine-secreting cells. Intracellular staining revealed that GATA-3 levels in freshly isolated naive CD8؉ T cells correlated with specific clinical manifestations. We therefore assessed the effects of GATA-3 inhibition on IL-13 production in CD8؉ T cells from the SSc patients.Results. Freshly isolated naive peripheral blood CD8؉ T cells expressed high levels of GATA-3 and failed to down-regulate IL-13 production when cultured under type 1-skewing conditions, but maintained adequate levels of interferon-␥ production. Cellular GATA-3 levels were significantly higher in patients with dcSSc and early inflammatory disease. Silencing of GATA-3 with small interfering RNA significantly reduced IL-13 production by CD8؉ T cells, demonstrating a causal relationship between GATA-3 and IL-13.Conclusion. These results provide important new insights into SSc pathogenesis and suggest that increased GATA-3 expression in CD8؉ T cells could be a highly relevant biomarker of immune dysfunction in patients with dcSSc. GATA-3 could be a novel therapeutic target for this currently incurable disease.

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REGULATION OF TH2 DIFFERENTIATION ANDIl4LOCUS ACCESSIBILITY

Cited by 589 publications

References 259 publications

Sex specifically associated promoter polymorphism in multiple sclerosis affects interleukin 4 expression levels

Sex specifically associated promoter polymorphism in multiple sclerosis affects interleukin 4 expression levels

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

GATA-3 up-regulation in CD8+ T cells as a biomarker of immune dysfunction in systemic sclerosis, resulting in excessive interleukin-13 production

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