Laboratory of Lymphocyte Biology, Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, MA 02115, USA.
J Exp Med. 2012 Aug 27;209(9):1529-35. doi: 10.1084/jem.20112646. Epub 2012 Aug 20.
Regulatory T cells (T reg cells) are essential for the prevention of autoimmunity throughout life. T reg cell development occurs intrathymically but a subset of T reg cells can also differentiate from naive T cells in the periphery. In vitro, Smad signaling facilitates conversion of naive T cells into T reg cells but results in unstable Foxp3 expression. The TGF-β-Smad response element in the foxp3 locus is located in the CNS1 region in close proximity to binding sites for transcription factors implicated in TCR and retinoic acid signaling. From in vitro experiments it was previously postulated that foxp3 transcription represents a hierarchical process of transcription factor binding in which Smad3 would play a central role in transcription initiation. However, in vitro conditions generate T reg cells that differ from T reg cells encountered in vivo. To address the relevance of Smad3 binding to the CNS1 enhancer in vivo, we generated mice that exclusively lack the Smad binding site (foxp3(CNS1mut)). We show that binding of Smad3 to the foxp3 enhancer is dispensable for T reg cell development in newborn and adult mice with the exception of the gut.
调节性 T 细胞（Treg 细胞）对于终生预防自身免疫至关重要。Treg 细胞的发育发生在胸腺内，但一部分 Treg 细胞也可以在外周从幼稚 T 细胞分化而来。在体外，Smad 信号促进幼稚 T 细胞向 Treg 细胞转化，但导致 Foxp3 表达不稳定。Foxp3 基因座中的 TGF-β-Smad 反应元件位于 CNS1 区域，靠近涉及 TCR 和视黄酸信号的转录因子结合位点。先前从体外实验中推测，Foxp3 转录代表转录因子结合的层次过程，其中 Smad3 在转录起始中发挥核心作用。然而，体外条件产生的 Treg 细胞与体内遇到的 Treg 细胞不同。为了解决 Smad3 与 CNS1 增强子结合在体内的相关性，我们生成了专门缺乏 Smad 结合位点的小鼠（foxp3(CNS1mut)）。我们表明，Smad3 与 foxp3 增强子的结合对于新生和成年小鼠的 Treg 细胞发育是可有可无的，除了肠道。
