T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on <i>IFNG</i> gene acetylation and transcription

Usui, Takashi; Preiß, J; Kanno, Yuka; Yao, Zheng Ju; Bream, Jay H.; O’Shea, John J.; Strober, Warren

doi:10.1084/jem.20052165

Cited by 294 publications

(278 citation statements)

References 32 publications

(59 reference statements)

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“…Recent data have suggested a different scenario for the development of Th1 and Th2 cells (32). It has been argued that the main role of T-bet is to negatively regulate GATA-3 function, rather than to positively regulate the IFN-␥ gene (32).…”

Section: Discussionmentioning

confidence: 99%

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Temporal Dissection of T-bet Functions

Matsuda

George²,

Hagman

et al. 2007

The Journal of Immunology

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T-bet is a transcription factor of the T-box family that regulates the expression of numerous immune system-associated genes. T-bet directs the acquisition of the Th1-associated genetic program in differentiating CD4+ lymphocytes. It also influences the development of NK and NKT cells through its regulation of the IL-2/IL-15Rβ-chain (CD122) and the trafficking of these lymphocytes through CxCR3. The temporal requirements of T-bet activity for the production of IFN-γ and the regulation of CD122 and CxCR3 expression remain undefined. We produced an ectopically controllable form of T-bet by fusing its C-terminal domain with a mutated ligand-binding domain of human estrogen receptor α. By temporally controlling the expression of T-bet-estrogen receptor α by the addition or removal of 4-hydroxytamoxifen (4-HT), we show that IFN-γ, CD122, and CxCR3 are direct gene targets of T-bet whose expression are acutely regulated by T-bet activity.

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Section: Discussionmentioning

confidence: 99%

“…It has been argued that the main role of T-bet is to negatively regulate GATA-3 function, rather than to positively regulate the IFN-␥ gene (32). Such inhibition was proposed to relieve the inhibition of STAT4 imposed by GATA-3 in Th2 cells (33).…”

Section: Discussionmentioning

confidence: 99%

Temporal Dissection of T-bet Functions

Matsuda

George²,

Hagman

et al. 2007

The Journal of Immunology

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“…Indeed, Eomes can be expressed by T-bet-deficient T cells and partially replace T-bet function (8,23,24,57). Although T-bet is not required for Eomes expression, it can enhance it by preventing the expression of known inhibitors of Eomes such as GATA3 (9,23,60). According to redundant functions between Eomes and T-bet, we did not observe differences in the accumulation of Eomes-deficient Th1 cells under inflammatory conditions or under steady state, despite the fact that the majority of Eomes + WT cells under those conditions were active producers of IFN-g.…”

Section: Discussionmentioning

confidence: 99%

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

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“…38,39 The formation of heterodimeric complexes leads to crossinhibition between master transcription factors. [40][41][42] When these biochemical properties are modelled mathematically, the resulting model includes high and low stable expression states 9,10 (see Box 1). The type of epigenetic modification that we model is CpG methylation, as this is one of the principle mechanisms of heritable epigenetic modification.…”

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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T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription

Cited by 294 publications

References 32 publications

Temporal Dissection of T-bet Functions

Temporal Dissection of T-bet Functions

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

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

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