title: Notch activation on effector T cells increases their sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression.
abstract: 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 ligands Delta-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.
authors.affiliation: INSERM, Unite U955, Creteil, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hue
authors.forename: Hassen
authors.initials: H
authors.lastname: Kared
authors.forename: Younas
authors.initials: Y
authors.lastname: Mehwish
authors.forename: Shahul
authors.initials: S
authors.lastname: Mouhamad
authors.forename: Michelle
authors.initials: M
authors.lastname: Balbo
authors.forename: Yves
authors.initials: Y
authors.lastname: Levy
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology; D002135:Calcium-Binding Proteins / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology; D000072100:Jagged-1 Protein; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051881:Receptor, Notch1 / Q000276:immunology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D051881:Receptor, Notch1; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D000072099:Serrate-Jagged Proteins; D051785:Smad Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497762:Notch1 protein, mouse