DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells
DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells
复制标题
DOI：
10.1002/eji.200737594
复制
发表时间：
2007-09-01
影响因子：
5.4
通讯作者：
Huehn, Jochen
中科院分区：
文献类型：
--
作者：
Baron, Udo;Floess, Stefan;Huehn, Jochen
转录因子FOXP3对调节性T细胞(Treg)的发育和功能至关重要。它们的数量和功能似乎在预防自身免疫和过敏方面至关重要，但也是各种实体肿瘤的负面预后标记物。虽然转录因子FOXP3的表达是目前已知的Treg的最好标志，但在人类中，也可以观察到激活的非Treg的瞬时表达。扩展我们最近对小鼠FOXP3基因座的发现，我们观察到人类FOXP3基因座中几个区域的表观遗传修饰仅在Treg中发生。重要的是，激活的常规CD4(+)T细胞和经转化生长因子-β处理的细胞尽管表达FOXP3，但没有显示FOXP3 DNA去甲基化，而Treg亚群即使在扩大的体外扩增中也保持稳定的去甲基化。为了研究全套基因是否可能在Treg谱系中有表观遗传印记，我们进行了全基因组差异甲基化杂交分析。在Treg和传统T细胞之间发现了几个不同的甲基化基因，但当在广泛的细胞和组织中进行测试时，除了FOXP3之外，没有一个基因完全是Treg所特有的。我们的结论是，FOXP3 DNA去甲基化是目前可用的最可靠的天然Treg标准。
The transcription factor FOXP3 is critical for development and function of regulatory T cells (Treg). Their number and functioning appears to be crucial in the prevention of autoinmumity and allergy, but also to be a negative prognostic marker for various solid tumors. Although expression of the transcription factor FOXP3 currently constitutes the best-known marker for Treg, in humans, transient expression is also observed in activated non-Treg. Extending our recent findings for the murine foxp3 locus, we observed epigenetic modification of several regions in the human FOXP3 locus exclusively occurring in Treg. Importantly, activated conventional CD4(+) T cells and TGF-beta-treated cells displayed no FOXP3 DNA demethylation despite expression of FOXP3, whereas subsets of Treg stable even upon extended in vitro expansion remained demethylated. To investigate whether a whole set of genes might be epigenetically imprinted in the Treg lineage, we conducted a genome-wide differential methylation hybridization analysis. Several genes were found displaying differential methylation between Treg and conventional T cells, but none beside FOXP3 turned out to be entirely specific to Treg when tested on a broad panel of cells and tissues. We conclude that FOXP3 DNA demethylation constitutes the most reliable criterion for natural Treg available at present.