Notch activation on effector T cells increases their sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression

Eur J Immunol. 2012 Jul;42(7):1796-803. doi: 10.1002/eji.201142330. Epub 2012 Jun 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / immunology
  • Calcium-Binding Proteins / immunology
  • Humans
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins / immunology
  • Jagged-1 Protein
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / immunology
  • Membrane Proteins / immunology
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / immunology*
  • RNA / chemistry
  • RNA / genetics
  • Receptor, Notch1 / immunology*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Smad Proteins / genetics
  • Smad Proteins / immunology*
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • Transcriptional Activation
  • Up-Regulation

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • Notch1 protein, mouse
  • Receptor, Notch1
  • Receptors, Transforming Growth Factor beta
  • Serrate-Jagged Proteins
  • Smad Proteins
  • RNA
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II