The Runx1 Transcription Factor Inhibits the Differentiation of Naive CD4<b>+</b> T Cells into the Th2 Lineage by Repressing <i>GATA3</i> Expression

Komine, Okiru; Hayashi, Keitaro; Natsume, Waka; Watanabe, Toshio; Seki, Youichi; Seki, Nobuhiko; Yagi, Ryoji; Sukzuki, Wataru; Tamauchi, Hidekazu; Hozumi, Katsuto; Habu, Sonoko; Kubo, Masato; Satake, Masanobu

doi:10.1084/jem.20021200

Cited by 113 publications

(99 citation statements)

References 45 publications

(52 reference statements)

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“…1B). Overexpression of RUNX1 promotes Th1 differentiation by repressing GATA-3, and there is evidence that it may also bind to the IL-4 silencer (23,36,37) To gain a better impression of the cellular functions regulated by T-bet, we used gene ontology (GO) to assign functions to our set of T-bet target genes. This revealed that the set of genes targeted by T-bet were enriched for those involved in metabolism (369 genes, P ϭ 6.4 ϫ 10 Ϫ8 ), RNA processing (34 genes, P ϭ 2.4 ϫ 10 Ϫ5 ), protein localization (43 genes, P ϭ 6.6 ϫ 10 Ϫ8 ), and transcription from RNA polymerase II promoters (37 genes, 9.9 ϫ 10 Ϫ4 ).…”

Section: Resultsmentioning

confidence: 99%

The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes

Jenner

Townsend

Jackson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

204

205

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Upon detection of antigen, CD4 ؉ T helper (Th) cells can differentiate into a number of effector types that tailor the immune response to different pathogens. Alternative Th1 and Th2 cell fates are specified by the transcription factors T-bet and GATA-3, respectively. Only a handful of target genes are known for these two factors and because of this, the mechanism through which T-bet and GATA-3 induce differentiation toward alternative cell fates is not fully understood. Here, we provide a genomic map of T-bet and GATA-3 binding in primary human T cells and identify their target genes, most of which are previously unknown. In Th1 cells, T-bet associates with genes of diverse function, including those with roles in transcriptional regulation, chemotaxis and adhesion. GATA-3 occupies genes in both Th1 and Th2 cells and, unexpectedly, shares a large proportion of targets with T-bet. Re-complementation of T-bet alters the expression of these genes in a manner that mirrors their differential expression between Th1 and Th2 lineages. These data show that the choice between Th1 and Th2 lineage commitment is the result of the opposing action of T-bet and GATA-3 at a shared set of target genes and may provide a general paradigm for the interaction of lineage-specifying transcription factors.Genomic map ͉ T helper differentiation ͉ cytokines

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Section: Resultsmentioning

confidence: 99%

The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes

Jenner

Townsend

Jackson³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

204

205

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“…It is clear that the IL-27/WSX-1 interaction occurs early on in the immune response and probably there are a number of type-1-promoting transcription factors that may play an important role in chronic infection, e.g., suppressor of cytokine signaling proteins, class II transactivator, friend of GATA-1, and Runx1 (17)(18)(19)29), although their relationship to WSX-1 is as yet undefined. Moreover, recent evidence is emerging demonstrating that Toll-like receptor (TLR) signaling pathways play an important role in determining the outcome of T. muris infection.…”

Section: Discussionmentioning

confidence: 99%

WSX-1: A Key Role in Induction of Chronic Intestinal Nematode Infection

Bancroft

Humphreys

Worthington

et al. 2004

The Journal of Immunology

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Chronic infection by the gastrointestinal nematode Trichuris muris in susceptible AKR mice, which mount a Th1 response, is associated with IL-27p28 expression in the cecum. In contrast to wild-type mice, mice that lack the WSX-1/IL-27R gene fail to harbor a chronic infection, having significantly lower Th1 responses. The lower level of Ag-specific IFN-γ-positive cells in WSX-1 knockout (KO) mice was found to be CD4+ T cell specific, and the KO mice also had increased levels of IL-4-positive CD4+ T cells. Polyclonal activation of mesenteric lymph node cells from naive WSX-1 KO or wild-type mice demonstrated that there was no inherent defect in the production of IFN-γ by CD4+ T cells, suggesting the decrease in these cells seen in infected WSX-1 KO mice is an in vivo Ag-driven effect. IL-12 treatment of WSX-1 KO mice failed to rescue the type 1 response, resulting in unaltered type-2-driven resistance. Infection of WSX-1 KO mice was also associated with a reduction of IL-27/WSX-1 downstream signaling gene expression within the cecum. These studies demonstrate an important role for WSX-1 signaling in the promotion of type 1 responses and chronic gastrointestinal nematode infection.

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“…First, IL-2 production is the crucial mechanism of T-cell activation. Second, IL2 transcription is known to be regulated by several key transcription factors, one of which is AML1/ RUNX1, a well-established downstream target of BMP signalling in hematopoietic lineage cells [8,14,15].…”

Section: A Complex Effect Of Dm On Il-2 Production Of T Cellsmentioning

confidence: 99%

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

et al. 2011

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Bone morphogenetic proteins (BMPs) are involved in patterning and cellular fate in various organs including the thymus. However, the redundancy of BMPs and their receptors have made it difficult to analyse their physiological roles. Here, we investigated the role of BMP signalling in peripheral CD4 1 T cells by analysing the effects of an inhibitor of BMP signalling, dorsomorphin. Dorsomorphin suppressed phosphorylation of SMAD1/5/8, suggesting that BMP signalling naturally occurs in T cells. At high doses, dorsomorphin suppressed proliferation of T cells in a dose-dependent manner, inducing G1 arrest. Also, dorsomorphin suppressed Th17 and induced Treg-cell differentiation, while preserving Th2 differentiation. Dorsomorphin efficiently suppressed IL-2 production even at low doses in mouse CD4 1 T cells, suggesting that the BMP-Smad signalling physiologically regulates IL-2 transcription in these cells. In addition, recombinant BMP2 induced a dosedependent multiphasic pattern of IL-2 production, while Noggin suppressed IL-2 production at higher doses in Jurkat cells. Notably, BMP signalling controlled the phosphorylation of RUNX1, revealing the molecular nature of its effect. Collectively, we describe multiple effects of dorsomorphin and Noggin on T-cell activation and differentiation, demonstrating a physiological role for BMP signalling in these processes.

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The Runx1 Transcription Factor Inhibits the Differentiation of Naive CD4+ T Cells into the Th2 Lineage by Repressing GATA3 Expression

Cited by 113 publications

References 45 publications

The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes

The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes

WSX-1: A Key Role in Induction of Chronic Intestinal Nematode Infection

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

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