title: Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction.
abstract: Notch1 signaling is involved in regulatory T (Treg)-cell differentiation. We previously demonstrated that, when cocultured with CD3(+)  cells, mesenchymal stem cells (MSCs) induced a T-cell population with a regulatory phenotype. Here, we investigated the molecular mechanism underlying MSC induction of human Treg cells. We show that the Notch1 pathway is activated in CD4(+)  T cells cocultured with MSCs. Inhibition of Notch1 signaling through GSI-I or the Notch1 neutralizing antibody reduced expression of HES1 (the Notch1 downstream target) and the percentage of MSC-induced CD4(+) CD25(high) FOXP3(+)  cells in vitro. Moreover, we demonstrate that FOXP3 is a downstream target of Notch signaling in human cells. No crosstalk between Notch1 and TGF-β signaling pathways was observed in our experimental system. Together, these findings indicate that activation of the Notch1 pathway is a novel mechanism in the human Treg-cell induction mediated by MSCs.
authors.affiliation: Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Del Papa
authors.forename: Paolo
authors.initials: P
authors.lastname: Sportoletti
authors.forename: Debora
authors.initials: D
authors.lastname: Cecchini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Rosati
authors.forename: Chiara
authors.initials: C
authors.lastname: Balucani
authors.forename: Stefano
authors.initials: S
authors.lastname: Baldoni
authors.forename: Katia
authors.initials: K
authors.lastname: Fettucciari
authors.forename: Pierfrancesco
authors.initials: P
authors.lastname: Marconi
authors.forename: Massimo F
authors.initials: MF
authors.lastname: Martelli
authors.forename: Franca
authors.initials: F
authors.lastname: Falzetti
authors.forename: Mauro
authors.initials: M
authors.lastname: Di Ianni
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D018655:Lymphocyte Count; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D000072056:Transcription Factor HES-1
chemical_list: D019138:Antibodies, Blocking; D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D053645:Interleukin-2 Receptor alpha Subunit; D009842:Oligopeptides; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C418974:FOXP3 protein, human; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; C078493:HES1 protein, human