Notch1 and TGFβ1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells
Notch1 and TGFβ1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cells
复制标题
DOI：
10.1182/blood-2008-03-144980
复制
发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Osborne, Barbara A.
中科院分区：
文献类型：
--
作者：
Samon, Jeremy B.;Champhekar, Ameya;Osborne, Barbara A.
Notch及其配体参与了多种CD 4（+）T辅助细胞的调节和分化。表达转录因子Foxp 3的调节性T细胞（T-CTL）抑制通常与自身免疫或过度炎症相关的异常免疫应答。以前的研究表明，转化生长因子β（TGF β 1）诱导Foxp 3表达和外周T细胞中的调节表型。在这里，我们表明使用γ-分泌酶抑制剂（GSI）处理的Notch信号传导的药理学抑制阻断（1）TGF β 1诱导的Foxp 3表达，（2）Foxp 3靶基因的上调，和（3）抑制幼稚T细胞增殖的能力。此外，Notch 1、CSL和Smad与foxp 3启动子中的保守结合位点的结合可以通过用GSI处理来抑制。最后，GSI的体内施用导致Foxp 3表达减少和与自身免疫性肝炎一致的症状的发展，所述自身免疫性肝炎是先前发现由TGF β信号传导和调节性T细胞的失调引起的疾病。总之，这些发现表明Notch和TGF β信号传导途径在体外和体内协同调节Foxp 3表达和调节性T细胞维持。
Notch and its ligands have been implicated in the regulation and differentiation of various CD4(+) T-helper cells. Regulatory T cells (T-regs), which express the transcription factor Foxp3, suppress aberrant immune responses that are typically associated with autoimmunity or excessive inflammation. Previous studies have shown that transforming growth factor beta (TGF beta 1) induces Foxp3 expression and a regulatory phenotype in peripheral T cells. Here, we show that pharmacologic inhibition of Notch signaling using, gamma-secretase inhibitor (GSI) treatment blocks (1) TGF beta 1-induced Foxp3 expression, (2) the up-regulation of Foxp3-target genes, and (3) the ability to suppress naive T-cell proliferation. In addition, the binding of Notch1, CSL, and Smad to conserved binding sites in the foxp3 promoter can be inhibited by treatment with GSI. Finally, in vivo administration of GSI results in reduced Foxp3 expression and development of symptoms consistent with autoimmune hepatitis, a disease previously found to result from dysregulation of TGF beta signaling and regulatory T cells. Together, these findings indicate that the Notch and TGF beta signaling pathways cooperatively regulate Foxp3 expression and regulatory T-cell maintenance both in vitro and in vivo.