Stat6-Independent GATA-3 Autoactivation Directs IL-4-Independent Th2 Development and Commitment

Ouyang, Wenjun; Löhning, Max; Gao, Zhiguang; Assenmacher, Mario; Ranganath, Sheila; Radbruch, Andreas; Murphy, Kenneth M.

doi:10.1016/s1074-7613(00)80156-9

Cited by 622 publications

(586 citation statements)

References 46 publications

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“…However, an alternative Th2 developmental pathway independent of IL-4-mediated signaling has been demonstrated in parasitic infection and antigenic stimulation systems (23)(24)(25). Thus, we next analyzed Th1 and Th2 cytokine production in activated T cells from spleens of STAT6 Ϫ/Ϫ NC and control mice.…”

Section: Resultsmentioning

confidence: 99%

Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice

Yagi

Nagai

Iigo

et al. 2002

The Journal of Immunology

121

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Atopic dermatitis (AD) is a pruritic inflammatory skin disease characterized by elevation of plasma levels of total IgE, infiltration of mast cells and eosinophils, and the expression of cytokines by Th2 T cells. However, the role of Th2 cells in the pathogenesis of AD is not fully understood. In this study we examined the NC/Nga (NC) mouse model of AD and established STAT6-deficient (SATA6−/−) NC mice to investigate the relevance of IL-4-mediated immune responses. Surprisingly, these mice elicited AD-like skin lesions at equivalent frequency and time of onset compared with normal NC littermates. Histological features of the lesion in STAT6−/− NC mice fulfilled the criteria for the pathogenesis of AD, although these mice fail to produce IgE and Th2 cytokines. The lymph nodes proximal to the regions of skin that developed lesions exhibited massive enlargement elicited by the accumulation of activated IFN-γ-secreting T cells. Moreover, caspase I, IL-18, IL-12, and IFN-γ are found to be highly expressed at the skin lesion, occurring simultaneously with elevation of eotaxin 2 and CCR3 expression. Therefore, the Th2-mediated immune response is not necessary for the development of AD-like skin disease in NC mice. The skin microenvironment that favored IFN-γ production tightly correlates with the skin disease in NC mice through the infiltration of eosinophils.

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Section: Resultsmentioning

confidence: 99%

Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice

Yagi

Nagai

Iigo

et al. 2002

The Journal of Immunology

121

View full text Add to dashboard Cite

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“…These results suggest that initiation of a Th2-type inflammatory response may not require IL-4, as Ag stimulation alone is sufficient. Indeed, a number of groups have reported the existence of IL-4-independent IL-4-producing cells (18,(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

IL-4 Induces Differentiation and Expansion of Th2 Cytokine-Producing Eosinophils

Chen

Grabowski

Xin

et al. 2004

The Journal of Immunology

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Innate effector cells that produce Th2-type cytokines are critical in Th2 cell-mediated immune responses. However, it is not known how these cells acquire the ability to produce Th2 cytokines. IL-4 is a potent inducer that directs differentiation of naive CD4+ T cells into CD4+ Th2 effector cells. To determine whether IL-4 can induce differentiation and expansion of Th2 cytokine-producing innate cells, we used mice whose il-4 gene was replaced by a knock-in green fluorescence protein (gfp) gene. We found that, directly ex vivo, IL-4 increased the number of GFP+ cells in the airway and the lung tissue in an Ag-specific manner. The majority of GFP+ cells were eosinophils, suggesting that IL-4 plays a pivotal role in expanding IL-4-producing eosinophils in vivo. IL-4-producing eosinophils showed some unique features compared with IL-4-producing CD4+ T cells. They exhibited biallelic expression of the il-4 gene when stimulated and were more dominant IL-4- and IL-5-producing cells. Furthermore, we show that IL-4 drove bone marrow progenitor cells to differentiate into Th2 cytokine-producing eosinophils in vitro. These results strongly suggest IL-4 is a potent factor in directing bone marrow progenitor cells to differentiate into Th2 cytokine-producing eosinophils.

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“…This allows that is, to have positive feedback on their own expression. 36,37 Additionally, experiments have shown that master transcription factors form homodimers facilitating cooperative binding to DNA. 38,39 The formation of heterodimeric complexes leads to crossinhibition between master transcription factors.…”

Section: Box 1 Positive Feedback Creates Attractorsmentioning

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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Stat6-Independent GATA-3 Autoactivation Directs IL-4-Independent Th2 Development and Commitment

Cited by 622 publications

References 46 publications

Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice

Development of Atopic Dermatitis-Like Skin Lesions in STAT6-Deficient NC/Nga Mice

IL-4 Induces Differentiation and Expansion of Th2 Cytokine-Producing Eosinophils

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

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