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

Authors

  • Sophie Hue,

    1. INSERM, Unite U955, Creteil, France
    2. Faculte de Medecine, Universite Paris-Est, Creteil, France
    3. AP-HP, Groupe Henri-Mondor Albert-Chenevier, Immunologie biologique, Creteil, France
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    • These authors have contributed equally to this work.

  • Hassen Kared,

    1. INSERM, Unite U955, Creteil, France
    2. Faculte de Medecine, Universite Paris-Est, Creteil, France
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    • These authors have contributed equally to this work.

  • Younas Mehwish,

    1. INSERM, Unite U955, Creteil, France
    2. Faculte de Medecine, Universite Paris-Est, Creteil, France
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  • Shahul Mouhamad,

    1. INSERM, Unite U955, Creteil, France
    2. Faculte de Medecine, Universite Paris-Est, Creteil, France
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  • Michelle Balbo,

    1. INSERM, Unite U955, Creteil, France
    2. Faculte de Medecine, Universite Paris-Est, Creteil, France
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  • Yves Levy

    Corresponding author
    1. Faculte de Medecine, Universite Paris-Est, Creteil, France
    2. AP-HP, Groupe Henri-Mondor Albert-Chenevier, Immunologie clinique, Creteil, France
    • INSERM, Unite U955, Creteil, France
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Full Correspondence: Prof. Yves Lévy, Service d'Immunologie Clinique, Hôpital Henri Mondor and INSERM U955 and University Paris Est, Créteil, France

Fax: +33-1-49812469

e-mail: yves.levy@hmn.aphp.fr

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.

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