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

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-beta RII expression and increased levels of the phosphorylated form of the Smad 3 protein. This effect is relieved by anti-TGF-beta Abs. We demonstrate that HES (hairy and enhancer of split), the main transcription factor downstream of Notch, induces strong transactivation of TGF-beta RII by binding the TGF-beta RII promoter through its DNA-binding domain. Thus, the crosstalk between Notch and the TGF-beta pathway leads to potentiation of the suppressive effect of Treg cells.