INSERM, Unite U955, Creteil, France.
Eur J Immunol. 2012 Jul;42(7):1796-803. doi: 10.1002/eji.201142330. Epub 2012 Jun 5.
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.
Notch 蛋白在胚胎发育和细胞命运决定中发挥重要作用。Notch 还影响外周 T 细胞的激活和分化。在这里，我们研究了 Notch 信号是否调节效应 T 细胞对调节性 T（Treg）细胞的反应。CD4(+)CD25(-)效应 T 细胞预先暴露于 Notch 配体 Delta-4 和 Jagged-1，但不是 Delta-1，通过上调 TGF-βRII 表达和增加磷酸化形式的 Smad 3 蛋白水平，显著增加了效应 T 细胞对 Treg 细胞介导的抑制的敏感性。这种效应可以通过抗 TGF-βAbs 缓解。我们证明，Notch 的主要转录因子 HES（头发和分裂增强子）通过其 DNA 结合域结合 TGF-βRII 启动子，诱导 TGF-ßRII 的强烈反式激活。因此，Notch 和 TGF-β 通路之间的串扰导致 Treg 细胞抑制作用的增强。
