Notch Directly Regulates Gata3 Expression during T Helper 2 Cell Differentiation

Fang, Terry; Yashiro–Ohtani, Yumi; Bianco, Cristina Del; Knoblock, Dawson; Blacklow, Stephen C.; Pear, Warren S.

doi:10.1016/j.immuni.2007.04.018

Cited by 326 publications

(330 citation statements)

References 52 publications

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“…However, distinct Notch receptors may have different effects on peripheral T cell responses. In two recent studies, Notch1 and Notch2 were shown to directly regulate GATA3 expression and to promote Th2-type polarization (29,30). In another study, CD4 ϩ T cells isolated from transgenic mice expressing a Notch1 antisense construct produced reduced amounts of IFN-␥ (15).…”

Section: Discussionmentioning

confidence: 99%

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Juryńczyk

Jurewicz

Raine

et al. 2008

The Journal of Immunology

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Among its varied functions, Notch signaling is involved in peripheral T cells responses. The activation and polarization of CD4+ T cells toward a Th1 lineage are essential steps in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Inhibition of all four Notch receptors with a γ-secretase inhibitor was shown to block Th1-type polarization and to attenuate the symptoms of experimental autoimmune encephalomyelitis. In this study, we have examined the role of individual Notch receptors in proliferation, cytokine production, and encephalitogenic potential of PLP-reactive T cells. Specific induction of Notch1 and Notch3 transcripts were noted in PLP-reactive T cells upon Ag stimulation. However, using γ-secretase inhibitor and Abs blocking distinct Notch receptors, we have found that selective inhibition of Notch3, but not Notch1, receptor abrogated proliferation, Th1- and Th17-type responses of PLP-reactive T cells. Moreover, Notch3 inhibition in T cells correlated with the down-regulated expression of protein kinase Cθ, a kinase with important regulatory function within mature T cells. Thus, selective inhibition of the Notch3 receptor may have important effects on peripheral T cell responses and may offer a new attractive target in treating autoimmune diseases, including multiple sclerosis.

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Section: Discussionmentioning

confidence: 99%

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Juryńczyk

Jurewicz

Raine

et al. 2008

The Journal of Immunology

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“…CD25 (IL2-R and preTa, pre-T-cell receptor alphachain) were also shown to be Notch target genes in T-cells [19,20]. In later stages of T-cell development, the transcription factor GATA3, a master regulator for Tcell development and later for Th1/2 lineage decision, is a direct Notch target gene [21,22]. Flavell and colleagues could show that Th2-mediated immunity depends on either RBP-J or Notch [22] and that the GATA3 promoter contains bona fide RBP-J binding sites.…”

Section: Notch Target Genesmentioning

confidence: 99%

“…Flavell and colleagues could show that Th2-mediated immunity depends on either RBP-J or Notch [22] and that the GATA3 promoter contains bona fide RBP-J binding sites. In addition, the Pear lab demonstrated, that the expression of dominant-negative mastermindlike-1 (dnMAML) results in impaired GATA3 transcription levels and subsequently impaired IL4 production [21]. Two other Notch target genes, NRARP and Deltex-1 were shown to be potent negative regulators of Notch signaling [23,24].…”

Section: Notch Target Genesmentioning

confidence: 99%

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The Notch signaling pathway: Transcriptional regulation at Notch target genes

Borggrefe

Oswald

2009

Cell. Mol. Life Sci.

584

499

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. The Notch gene encodes a transmembrane receptor that gave the name to the evolutionary highly conserved Notch signaling cascade. It plays a pivotal role in the regulation of many fundamental cellular processes such as proliferation, stem cell maintenance and differentiation during embryonic and adult development. After specific ligand binding, the intracellular part of the Notch receptor is cleaved off and translocates to the nucleus, where it binds to the transcription factor RBP-J. In the absence of activated Notch, RBP-J represses Notch target genes by recruiting a corepressor complex. Here, we review Notch signaling with a focus on gene regulatory events at Notch target genes. This is of utmost importance to understand Notch signaling since certain RBP-J associated cofactors and particular epigenetic marks determine the specificity of Notch target gene expression in different cell types. We subsequently summarize the current knowledge about Notch target genes and the physiological significance of Notch signaling in development and cancer.

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“…Later studies showed that Notch was also involved in mammalian differentiation processes including those governing the development of the immune system (19). The latter included evidence for a role of Notch signaling in the intrathymic differentiation of T cells (20 -22) as well as Th cell development in the periphery (23)(24)(25)(26)(27). Notch is, like TGF-␤, an evolutionarily conserved molecule but, unlike TGF-␤, is a type I transmembrane receptor rather than a receptor ligand.…”

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confidence: 99%

Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.

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Notch Directly Regulates Gata3 Expression during T Helper 2 Cell Differentiation

Cited by 326 publications

References 52 publications

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

Notch3 Inhibition in Myelin-Reactive T Cells Down-Regulates Protein Kinase Cθ and Attenuates Experimental Autoimmune Encephalomyelitis

The Notch signaling pathway: Transcriptional regulation at Notch target genes

Notch1 Signaling and Regulatory T Cell Function

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