Mucosal Immunology Unit, Oral Infection and Immunity Branch, National Institutes of Health, Bethesda, Maryland, USA.
Nat Immunol. 2011 Jan;12(1):86-95. doi: 10.1038/ni.1965. Epub 2010 Dec 5.
The molecular mechanisms that direct transcription of the gene encoding the transcription factor Foxp3 in CD4(+) T cells remain ill-defined. We show here that deletion of the DNA-binding inhibitor Id3 resulted in the defective generation of Foxp3(+) regulatory T cells (T(reg) cells). We identify two transforming growth factor-β1 (TGF-β1)-dependent mechanisms that were vital for activation of Foxp3 transcription and were defective in Id3(-/-) CD4(+) T cells. Enhanced binding of the transcription factor E2A to the Foxp3 promoter promoted Foxp3 transcription. Id3 was required for relief of inhibition by the transcription factor GATA-3 at the Foxp3 promoter. Furthermore, Id3(-/-) T cells showed greater differentiation into the T(H)17 subset of helper T cells in vitro and in a mouse asthma model. Therefore, a network of factors acts in a TGF-β-dependent manner to control Foxp3 expression and inhibit the development of T(H)17 cells.
指导转录因子 Foxp3 基因在 CD4(+)T 细胞中转录的分子机制仍不清楚。我们在此表明，缺失 DNA 结合抑制剂 Id3 会导致 Foxp3(+)调节性 T 细胞（T(reg)细胞）的生成缺陷。我们确定了两种转化生长因子-β1 (TGF-β1) 依赖性机制，它们对 Foxp3 转录的激活至关重要，而在 Id3(-/-)CD4(+)T 细胞中则存在缺陷。转录因子 E2A 与 Foxp3 启动子的增强结合促进了 Foxp3 转录。Id3 对于减轻转录因子 GATA-3 在 Foxp3 启动子上的抑制作用是必需的。此外，Id3(-/-)T 细胞在体外和小鼠哮喘模型中显示出更多地分化为辅助性 T 细胞 TH17 亚群。因此，一系列因素以 TGF-β 依赖的方式作用，以控制 Foxp3 的表达并抑制 TH17 细胞的发育。
