Delta1-Notch3 Interactions Bias the Functional Differentiation of Activated CD4+ T Cells

Maekawa, Yoichi; Tsukumo, Shin-ichi; Chiba, Shigeru; Hirai, Hisamaru; Hayashi, Yuji; Okada, Hiroko; Kishihara, Kenji; Yasutomo, Koji

doi:10.1016/s1074-7613(03)00270-x

Cited by 265 publications

(302 citation statements)

References 45 publications

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“…Work regarding the regulation of the T-bet gene itself has been limited; we know it is positively regulated by the Notch1 transcription factor and by proinflammatory cytokines such as IL-12, IL-15 and IL-18 [1,3,4,14,15] and IFN-c [17], and negatively regulated by TGF-b [14,15,20]. Studies of the transcription factors activated by these cytokines suggest that STAT4-, STAT1-and SMADdependent and -independent mechanisms are likely involved in the regulation of T-bet [5,8,[14][15][16][18][19][20][21], but definitive characterizations of these and other potential regulatory pathways have not been reported.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that STAT may play a role in the regulation of this gene; however, the regulation of T-bet has been reported as both STAT4 dependent and STAT4 independent [5,7,16]. T-bet induces IFN-c that in turn positively regulates T-bet expression [17], but there is no consistent conclusion on whether the regulation is or is not mediated by STAT1 [5,8,16,18,19]. The anti-inflammatory cytokine TGF-b 1 has previously been shown to down-regulate T-bet [14,15,20], and in some but not all instances this is mediated by SMAD proteins [21].…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

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Murine T-bet (T-box expressed in T cells) is a master regulator of IFN-c gene expressionin NK and T cells. T-bet also plays a critical role in autoimmunity, asthma and other diseases. However, cis elements or trans factors responsible for regulating T-bet expression remain largely unknown. Here, we report on our discovery of six Sp1-binding sites within the proximal human T-BET promoter that are highly conserved among mammalian species. Electrophoretic mobility shift assays demonstrate a physical association between Sp1 and the proximal T-BET promoter with a direct dose response between Sp1 expression and T-BET promoter activity. Ectopic overexpression of Sp1 also enhanced T-BET expression and cytokine-induced IFN-c secretion in NK cells and T cells. Mithramycin A, which blocks the binding of Sp1 to the T-BET promoter, diminished both T-BET expression and IFN-c protein production in monokine-stimulated primary human NK cells. Collectively, our results suggest that Sp1 is a positive transcriptional regulator of T-BET. As T-BET and IFN-c are critically important in inflammation, infection, and cancer, targeting Sp1, possibly with mithramycin A, may be useful for preventing and/ or treating diseases associated with aberrant T-BET or IFN-c expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptional control of human T‐BET expression: The role of Sp1

Min

Boyd

et al. 2007

Eur J Immunol

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“…These results demonstrate that Notch signaling increases IL-7-driven thymocyte proliferation. A relationship between the density of Notch ligands, the intensity of Notch signaling, and cell proliferation has been described by several authors [18,19]. Therefore, we performed experiments in which CD34 1 TN thymocytes were plated with growing numbers of OP9-DL1 or OP9-DL4 cells.…”

Section: Ispmentioning

confidence: 96%

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

et al. 2009

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Notch and IL-7 are both well-characterized factors involved in T-cell development. In contrast to the mouse model, their precise requirements in the differentiation and/or proliferation of various stages of human thymic development have not been fully explored. Here, we demonstrate that IL-7 alone is sufficient to induce the differentiation of ex vivoimmature single positive (ISP) (sCD3 À CD4 1 CD8 À ) and double positive (DP) (sCD3 À CD4 1 CD8 1 ) human thymic precursors to mature DP expressing sCD3 (sCD3 1 CD4 1 CD8 1 ). We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34 1 TN and to a lesser extent of CD4 1 ISP precursors. This effect of Notch is related to a sustained induction of IL-7 receptor a chain expression on thymocytes through a decreased methylation of its gene promoter. Thus, we show here that proliferation and differentiation of T-cell precursors are differentially modulated by IL-7 depending on the presence or absence of external signals. These results may have important implications for the clinical use of this cytokine as a strategy aimed at improving immune restoration.

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“…We have also observed trisomy 8 in 4/7 (57%) MAs with SO (unpublished data). Consequently, copy number gains of MYBL1 may be a strong candidate for a recurrent driving event in the progression of MA to sarcomatous overgrowth.and MDM2 protein expression was always focal or diffusely weak in MA, in contrast to the typically strong and diffuse staining pattern seen in well-differentiated and dedifferentiated liposarcoma with high-level MDM2 and CDK4 amplification [42,43]. We note that two cases of MA have been reported to express MDM2 by immunohistochemistry (one with and one without SO) [15], corroborating our findings.…”

Section: Be Howitt Et Almentioning

confidence: 99%

Targeted genomic analysis of Müllerian adenosarcoma

Howitt

Sholl

Cin

et al. 2014

The Journal of Pathology

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Müllerian adenosarcoma (MA) is a rare mixed mesenchymal tumour of the female genital tract, composed of malignant stroma and benign-appearing epithelium. Sarcomatous overgrowth (SO) is the only established histological variable associated with higher stage and shorter survival. Specific molecular or immunohistochemistry (IHC) tools for the diagnosis of MA are lacking. Our goal was to study genomic mutations and copy number variations (CNVs) in MA to understand better its pathobiology, and develop specific diagnostic and prognostic tools. DNA was extracted from 20 samples of MA from 18 subjects (12 without SO and 6 with SO), including two in which areas of both typical MA histology and SO were independently tested. Samples were analysed using a targeted next-generation sequencing assay interrogating exonic sequences of 275 cancer genes for mutations and CNVs as well as 91 introns across 30 genes for cancer-associated rearrangements. The mean number of mutations in MA with SO (mean 9.7; range 3-14) did not differ significantly from that in MA without SO (mean 9.6; range 5-16). MA with SO had significantly higher mean numbers of gene-level CNVs (24.6) compared to MA without SO (5; p = 0.0002). The most frequent amplification involved MDM2 and CDK4 (5/18; 28%), accompanied by focal CDK4 and MDM2 and diffuse HMGA2 expression using immunohistochemistry. MYBL1 amplification was seen in 4/18 (22%), predominantly in SO. Alterations in PIK3CA/AKT/PTEN pathway members were seen in 13/18 (72%). Notably, TP53 mutations were uncommon, present in only two cases with SO. Three out of 18 (17%) had mutations in ATRX, all associated with SO. No chromosomal rearrangements were identified. We have identified a number of recurrent genomic alterations in MA, including some associated with SO. Although further investigation of these findings is needed, confirmation of one or more may lead to new mechanistic insights and novel markers for this often difficult-to-diagnose tumour.

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Delta1-Notch3 Interactions Bias the Functional Differentiation of Activated CD4+ T Cells

Cited by 265 publications

References 45 publications

Transcriptional control of human T‐BET expression: The role of Sp1

Transcriptional control of human T‐BET expression: The role of Sp1

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

Targeted genomic analysis of Müllerian adenosarcoma

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