Unstable FoxP3+ T regulatory cells in NZW mice
Unstable FoxP3+ T regulatory cells in NZW mice
复制标题
DOI：
10.1073/pnas.1524660113
复制
发表时间：
2016-02-02
影响因子：
11.1
通讯作者：
Benoist, Christophe
中科院分区：
文献类型：
--
作者：
Depis, Fabien;Kwon, Ho-Keun;Benoist, Christophe
表达转录因子FoxP 3的调节性T（Treg）细胞在自身耐受和炎症控制中起关键作用。在小鼠和人类中，Treg频率存在很大的个体间范围，但对潜在的遗传或表观遗传机制知之甚少。我们在近交系小鼠中探索了这个问题，特别关注在NZW小鼠中发现的Treg细胞比例低。混合骨髓嵌合体实验表明，这种缺乏是NZW Treg细胞固有的，这种缺乏可能与Treg库和FoxP 3表达的稳定性差有关。这种不稳定性不是差异表观遗传标记的结果，因为在Foxp 3位点的Treg特异性CpG低甲基化特征在所有测试菌株中相似。这也是无关的高表达的干扰素签名基因在NZW，所示的intercross与Ifnar 1敲除小鼠。NZW Tyndrome对限制剂量的营养细胞因子IL-2和-33的敏感性较低，用于群体稳态和维持FoxP 3表达。基因表达谱突出了与其他菌株相比，NZW Tyndrome的转录组中的特定差异，但没有单一的缺陷可以明显地解释不稳定性。相反，NZW TdR显示了Treg细胞中通常被抑制的转录物的普遍上调，我们推测这种网络水平的偏差可能是NZW Treg不稳定的原因。
Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability.