Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction

Authors

  • Beatrice Del Papa,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Paolo Sportoletti,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Debora Cecchini,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Emanuela Rosati,

    1. General Pathology and Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Chiara Balucani,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Stefano Baldoni,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Katia Fettucciari,

    1. General Pathology and Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Pierfrancesco Marconi,

    1. General Pathology and Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Massimo F. Martelli,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
  • Franca Falzetti,

    1. Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Mauro Di Ianni

    Corresponding author
    1. Department of Internal Medicine and Public Health, University of L'Aquila, L'Aquila, Italy
    • Hematology and Clinical Immunology Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy
    Search for more papers by this author
    • These authors contributed equally to this work.


Full Correspondence:Dr. Mauro Di Ianni, Chair of Hematology, Department of Internal Medicine and Public Health, University of L'Aquila, 67100 L'Aquila, Italy.

Fax: +39-075-5783219

e-mail: mauro.diianni@cc.univaq.it

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+CD25highFOXP3+ 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.

Ancillary