Notch1 modulates mesenchymal stem cells mediated regulatory T-cell induction

Eur J Immunol. 2013 Jan;43(1):182-7. doi: 10.1002/eji.201242643. Epub 2012 Dec 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Blocking / pharmacology
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CD4 Antigens / metabolism
  • Cell Differentiation
  • Cells, Cultured
  • Coculture Techniques
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Count
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / immunology*
  • Oligopeptides / pharmacology
  • Receptor, Notch1 / antagonists & inhibitors
  • Receptor, Notch1 / immunology
  • Receptor, Notch1 / metabolism*
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Transcription Factor HES-1


  • Antibodies, Blocking
  • Basic Helix-Loop-Helix Transcription Factors
  • CD4 Antigens
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Interleukin-2 Receptor alpha Subunit
  • Oligopeptides
  • Receptor, Notch1
  • Transcription Factor HES-1
  • benzyloxycarbonyl-leucyl-leucyl-norleucinal
  • HES1 protein, human