Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048;
J Immunol. 2014 Apr 15;192(8):3915-24. doi: 10.4049/jimmunol.1302174. Epub 2014 Mar 14.
Glucocorticoid-induced TNFR (Gitr) and Ox40, two members of the TNFR superfamily, play important roles in regulating activities of effector and regulatory T cells (Treg). Their gene expression is induced by T cell activation and further upregulated in Foxp3+ Treg. Although the role of Foxp3 as a transcriptional repressor in Treg is well established, the mechanisms underlying Foxp3-mediated transcriptional upregulation remain poorly understood. This transcription factor seems to upregulate expression not only of Gitr and Ox40, but also other genes, including Ctla4, Il35, Cd25, all critical to Treg function. To investigate how Foxp3 achieves such upregulation, we analyzed its activity on Gitr and Ox40 genes located within a 15.1-kb region. We identified an enhancer located downstream of the Gitr gene, and both Gitr and Ox40 promoter activities were shown to be upregulated by the NF-κB-mediated enhancer activity. We also show, using the Gitr promoter, that the enhancer activity was further upregulated in conjunction with Foxp3. Foxp3 appears to stabilize NF-κB p50 binding by anchoring it to the enhancer, thereby enabling local accumulation of transcriptional complexes containing other members of the NF-κB and IκB families. These findings may explain how Foxp3 can activate expression of certain genes while suppressing others.
糖皮质激素诱导的肿瘤坏死因子受体（Gitr）和 OX40 是肿瘤坏死因子受体超家族的两个成员，它们在调节效应器和调节性 T 细胞（Treg）的活性方面发挥着重要作用。它们的基因表达是由 T 细胞激活诱导的，并在 Foxp3+Treg 中进一步上调。尽管 Foxp3 作为 Treg 中的转录抑制因子的作用已得到充分证实，但 Foxp3 介导的转录上调的机制仍知之甚少。这种转录因子似乎不仅上调 Gitr 和 Ox40 的表达，还上调其他基因的表达，包括 Ctla4、Il35 和 Cd25，这些基因对 Treg 功能至关重要。为了研究 Foxp3 如何实现这种上调，我们分析了其在位于 15.1kb 区域内的 Gitr 和 Ox40 基因上的活性。我们确定了位于 Gitr 基因下游的增强子，并且 Gitr 和 Ox40 启动子活性都被 NF-κB 介导的增强子活性上调。我们还使用 Gitr 启动子表明，增强子活性与 Foxp3 一起进一步上调。Foxp3 通过将其锚定到增强子上，似乎稳定了 NF-κB p50 的结合，从而使包含 NF-κB 和 IκB 家族其他成员的转录复合物能够在局部积累。这些发现可能解释了 Foxp3 如何能够激活某些基因的表达，同时抑制其他基因的表达。
