Department of Biology and Biotechnology C. Darwin, University Sapienza of Rome, Italy.
Eur J Immunol. 2011 Feb;41(2):503-13. doi: 10.1002/eji.201040712. Epub 2011 Jan 11.
The molecular mechanisms whereby CD28 alone or associated with TCR can regulate FOXP3 expression are not understood, although the importance of CD28 as a pivotal regulator of CD4(+) CD25(+) FOXP3(+) T cells is well recognized. We previously demonstrated that unique CD28-induced, NF-κB-dependent signals were sufficient to activate FOXP3 transcription in human CD4(+) CD25(-) T cells; however, the exact mechanisms are currently unknown. In this study, we have identified novel κB-binding sites on FOXP3 gene and demonstrated that CD28 signals mediated FOXP3 trans activation by nuclear translocation of RelA/NF-κB and not of c-Rel. The occupancy of FOXP3 κB-binding sites by RelA dimers that correlated with histone acetylation and recruitment of Pol II were required both to initiate FOXP3 transcription and to control the promoter occupancy by NFAT. Interestingly, knockdown of RelA in CD4(+) CD25(-) T cells stimulated through TCR and CD28 significantly affected FOXP3 expression, confirming that also the transcriptional activation of FOXP3 gene by TCR in the presence of CD28-costimulatory signals is RelA-dependent. In conclusion, these data suggest a new mechanism by which FOXP3 is activated and supports the critical role of CD28 in the regulation of peripheral tolerance.
CD28 单独或与 TCR 结合调控 FOXP3 表达的分子机制尚不清楚，尽管 CD28 作为 CD4(+) CD25(+) FOXP3(+) T 细胞的关键调节因子的重要性已得到广泛认可。我们之前证明，独特的 CD28 诱导的 NF-κB 依赖性信号足以激活人 CD4(+) CD25(-) T 细胞中的 FOXP3 转录；然而，确切的机制目前尚不清楚。在这项研究中，我们已经确定了 FOXP3 基因上的新 κB 结合位点，并证明 CD28 信号通过 RelA/NF-κB 的核易位而不是 c-Rel 介导 FOXP3 的反式激活。RelA 二聚体与组蛋白乙酰化和 Pol II 的募集相关的 FOXP3 κB 结合位点的占据，对于启动 FOXP3 转录和控制 NFAT 对启动子的占据都是必需的。有趣的是，通过 TCR 和 CD28 刺激的 CD4(+) CD25(-) T 细胞中 RelA 的敲低显著影响 FOXP3 的表达，这证实了即使在存在 CD28 共刺激信号的情况下，TCR 也能依赖于 RelA 激活 FOXP3 基因的转录。总之，这些数据提出了一种 FOXP3 被激活的新机制，并支持 CD28 在调节外周耐受中的关键作用。
