Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells
Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells
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T 细胞谱系定型需要转录因子 KLF4 的下调
DOI：
10.1038/cr.2011.183
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发表时间：
2011-12-01
期刊：
影响因子：
44.1
通讯作者：
Liu, Xiaolong
中科院分区：
文献类型：
--
作者：
Wen, Xiaomin;Liu, Haifeng;Liu, Xiaolong
重编程因子Oct 4、Sox 2、c-Myc和Klf 4在早期T细胞发育中的作用尚未完全确定。在这里，我们表明，Klf 4是唯一的重编程因子，其表达下调时，早期胸腺祖细胞（ETP）分化为T细胞。Klf 4在未定型祖细胞中的强制表达严重损害了T细胞发育，主要是在T细胞谱系定型发生时的DN 2-至-DN 3转变，并影响了在早期T细胞发育中具有关键功能的多种基因的转录，包括参与微环境信号传导的基因（IL-7 R α）、Notch靶基因（Deltex 1）和必需的T细胞谱系调节或抑制基因（Bcl 11 a、SpiB和Id 1）。胸腺细胞的生存和重排在Tcrb基因座受损的存在下，强制Klf 4的表达。Klf 4转基因小鼠中DN 1-至-DN 2和DN 2-至-DN 3转换的缺陷不能通过引入TCR转基因来挽救，但可以通过恢复IL-7 R α的表达来部分挽救。因此，我们的数据表明Klf 4的下调是T细胞谱系定型的先决条件。
The roles of the reprogramming factors Oct4, Sox2, c-Myc and Klf4 in early T cell development are incompletely defined. Here, we show that Klf4 is the only reprogramming factor whose expression is downregulated when early thymic progenitors (ETPs) differentiate into T cells. Enforced expression of Klf4 in uncommitted progenitors severely impaired T cell development mainly at the DN2-to-DN3 transition when T cell lineage commitment occurs and affected the transcription of a variety of genes with crucial functions in early T cell development, including genes involved in microenvironmental signaling (IL-7Rα), Notch target genes (Deltex1), and essential T cell lineage regulatory or inhibitory genes (Bcl11a, SpiB, and Id1). The survival of thymocytes and the rearrangement at the Tcrb locus were impaired in the presence of enforced Klf4 expression. The defects in the DN1-to-DN2 and DN2-to-DN3 transitions in Klf4 transgenic mice could not be rescued by the introduction of a TCR transgene, but was partially rescued by restoring the expression of IL-7Rα. Thus, our data indicate that the downregulation of Klf4 is a prerequisite for T cell lineage commitment.