1. Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction
- Author
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DEL PAPA, Beatrice, Sportoletti, Paolo, Cecchini, Debora, Rosati, Emanuela, Balucani, Chiara, Baldoni, Stefano, Fettucciari, Katia, Marconi, Pierfrancesco, Martelli, Massimo Fabrizio, Falzetti, Franca, and DI IANNI, Mauro
- Subjects
Homeodomain Proteins ,Notch1 ,Immune regulation ,Interleukin-2 Receptor alpha Subunit ,Cell Differentiation ,Forkhead Transcription Factors ,Mesenchymal Stem Cells ,T-Lymphocytes, Regulatory ,Coculture Techniques ,Gene Expression Regulation ,T-Lymphocyte Subsets ,CD4 Antigens ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Transcription Factor HES-1 ,Immune regulation, Mesenchymal stem cells, Notch1, Tolerance, Treg cells ,Lymphocyte Count ,Receptor, Notch1 ,Antibodies, Blocking ,Tolerance ,Oligopeptides ,Treg cells ,Cells, Cultured ,Signal Transduction - 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.
- Published
- 2012