Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-

Ostroukhova, Marina; Qi, Zengbiao; Oriss, Timothy B.; Dixon-McCarthy, Barbara; Ray, Prabir; Ray, Anuradha

doi:10.1172/jci26490

Cited by 158 publications

(138 citation statements)

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“…With regard to these latter questions, recently it was shown that cells bearing surface TGF-␤ (but not cells that lacked this property) could activate the Notch1 signaling pathway in potential target cells (16). More importantly, the activity of regulatory cells that prevent the development of experimental asthma could be blocked in the whole animal by the administration of a blocking anti-Notch1 Ab (16).…”

Section: Discussionmentioning

confidence: 99%

“…Notch-1 Ab-1 (Clone A6) was purchased from Neomarkers; this Ab has been shown in previous studies to be a blocking Ab that inhibits Notch1 signaling (16,31). Abs for Notch ligands, multispecies TGF-␤1, 2, and 3 mAb (Clone 1D11), mouse IgG1, mouse IgG2b isotype control, and recombinant TGF-␤1 were purchased from R&D Systems.…”

Section: Abs and Reagentsmentioning

confidence: 99%

“…This possibility arises from several reports that overexpression of Notch ligand can induce regulatory cells (13)(14)(15); in addition, it has recently been shown that Tregs with membrane-bound TGF-␤ stimulate the Notch pathway and that such stimulation is necessary for the induction of tolerance to respiratory Ags in the airway (16). Notch is a phylogenetically old molecule that was first identified as a signaling component essential for the differentiation of the embryonic nervous system of Drosophila (17,18).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Abs and Reagentsmentioning

confidence: 99%

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confidence: 99%

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Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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“…It regulates multiple steps of T and B cell development, T cell activation, regulatory T-cell function and T-helper cell differentiation [7][8][9][10][11]. Furthermore, it helps in the development and differentiation of many other hematopoietic and immune cells [12].…”

Section: Introductionmentioning

confidence: 99%

Correlation of Notch1/Hes1 Genes Expression Levels in Egyptian Paediatric Patients with Newly Diagnosed and Persistent Primary Immune(Idiopathic) Thrombocytopenic Purpura

Gawdat

Hammam

Ezzat

2015

Indian J Hematol Blood Transfus

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Notch signalling is involved in the development of several autoimmune diseases, one of such diseases is ITP. The aim of this study was to investigate and compare the expression levels of Notch1 receptor and its target Hes1 gene in Egyptian paediatric ITP patients. Real-time quantitative reverse transcriptase polymerase chain reaction was used to analyse the expression levels of Notch1 and Hes1 in 42 children with primary ITP (22 newly diagnosed and 20 persistent) cases. Twenty age and sex matched non-ITP controls were included. The expression levels of Notch1 were higher in newly diagnosed and persistent cases than controls with high statistical significant difference (P value \ 0.001, P \ 0.001) respectively, similarly as regards the expression levels of HES1 (P value \ 0.001, P \ 0.007) respectively. A significant positive correlation was found between Notch1 and Hes1 expression levels in newly diagnosed cases (r = 0.587, P value = 0.004). There was an association between levels of both genes in most of ITP patients but Hes1 was markedly elevated than Notch1 in few cases. High expression levels of Notch1/Hes1 indicated the important role of Notch signalling in both newly diagnosed and persistent ITP. High expression levels of Hes1 than Notch1 may shed light on its value as a therapeutic target for future research in ITP.

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“…Notch pathways play an important role in embryonic development, T-cell development and function, and in disease processes, including carcinogenesis and autoimmunity. In mammals there are four Notch receptors (1)(2)(3)(4) and five Notch ligands (Jagged-1, Jagged-2, Delta-like 1 (DL-1), DL-3, and DL-4) [1].…”

Section: Introductionmentioning

confidence: 99%

Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

et al. 2012

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Notch proteins play an important role in embryonic development and cell-fate decisions. Notch influences also the activation and differentiation of peripheral T cells. Here, we investigated whether Notch signaling modulates the response of effector T cells to regulatory T (Treg) cells. Pre-exposure of CD4 + CD25 − effector T cells to the Notch ligandsDelta-4 and Jagged-1, but not Delta-1, increases significantly effector T-cell sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression and increased levels of the phosphorylated form of the Smad 3 protein. This effect is relieved by anti-TGF-β Abs. We demonstrate that HES (hairy and enhancer of split), the main transcription factor downstream of Notch, induces strong transactivation of TGF-ßRII by binding the TGF-βRII promoter through its DNA-binding domain. Thus, the crosstalk between Notch and the TGF-β pathway leads to potentiation of the suppressive effect of Treg cells. Keywords:Immune regulation r Notch signaling r Regulatory T cells r TGF-βRII IntroductionThe Notch signaling system is conserved from Drosophila to humans and regulates cell differentiation, proliferation, and survival. Notch pathways play an important role in embryonic development, T-cell development and function, and in disease processes, including carcinogenesis and autoimmunity. In mammals there are four Notch receptors (1-4) and five Notch ligands (Jagged-1, Jagged-2, Delta-like 1 (DL-1), [1].Notch proteins exert their pleiotropic effects through the regulation of expression of various downstream genes, many of which require the interaction of Notch proteins with the DNA binding transcription factor CSL (also known as CBF1, Su(H), Correspondence: Prof. Yves Levy e-mail: yves.levy@hmn.aphp.fr and LAG-1) in order to form a short-lived nuclear transcription complex [2]. After engagement with its ligands, successive proteolytic events cause clipping of the Notch protein. The first is mediated by ADAM proteases and the second by the γ-secretase complex, in which presenilins (PS1 and PS2) constitute the active center of the enzyme complex. These proteolytic events ultimately release the intracellular domain of Notch (NICD). The formation of a complex of activated intracellular Notch protein and CSL converts CSL from a transcriptional repressor to a transcriptional transactivator. The genes encoding the HES (hairy and enhancer of split) family of basic helix-loop-helix proteins are Notch targets that are known to be essential for T-cell development and signaling. * These authors have contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1796-1803 Immunomodulation 1797In addition to influencing , Notch signaling has also been involved in the differentiation and expansion of regulatory T (Treg) cells [4]. Several reports have shown that the presence of Notch ligands, mostly of the Jagged family, can enhance Treg-cell differentiation and function in vitro [5]. For example, exposure of Treg cells to Jagged-2 expressed by hematopoietic progen...

show abstract

Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-

Cited by 158 publications

References 46 publications

Notch1 Signaling and Regulatory T Cell Function

Notch1 Signaling and Regulatory T Cell Function

Correlation of Notch1/Hes1 Genes Expression Levels in Egyptian Paediatric Patients with Newly Diagnosed and Persistent Primary Immune(Idiopathic) Thrombocytopenic Purpura

Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

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