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Cell Res:刘小龙等揭示KLF4调控早期T细胞分化定向机制

来源:上海生命科学研究院 2011-11-30 19:53

11月22日,Cell Research在线发表了中科院上海生科院生化与细胞所刘小龙研究组的研究成果“Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells”,该工作揭示了转录因子KLF4对早期T细胞分化定向的调控机制。

已有研究表明,小鼠体细胞可以通过外源表达四个转录因子Klf4、Oct4、c-Myc、Sox2而诱导生成多潜能干细胞(iPS)。这些转录因子通过调控细胞转录网络来维持ES细胞的多潜能性和自我更新能力。但是,到目前为止仍然不够清楚的是,这四个转录因子在成体干细胞以及其向特异的细胞谱系分化时是否具有功能。

最近刘小龙研究组的博士研究生温晓敏等研究发现,在造血干细胞(HSC)分化为T细胞的过程中Klf4的表达发生特异变化,在向T细胞分化前持续表达,但是在向T细胞分化时Klf4表达则被关闭。在胸腺细胞中强制表达Klf4会严重影响DN2到DN3的分化进程,而此时正好是决定多潜能的胸腺祖先细胞是否最终定向分化为T细胞的关键时刻。强制表达Klf4会影响众多T细胞分化关键调控因子的表达,包括胸腺微环境信号分子(IL-7Ra)、Notch靶标(Deltex1)和转录调控因子(Bcl11a、SpiB、Id1)等。强制表达Klf4还会影响TCRb基因的DNA重排以及胸腺细胞的存活,但是仅引入TCR转基因并不能弥补其造成的分化缺陷。而通过恢复IL-7Ra的表达则能在一定程度上弥补在Klf4转基因鼠中存在的DN1-DN2 和DN2-DN3分化缺陷。该研究不仅揭示下调Klf4表达对于T细胞的早期分化定向极其重要,同时也拓展了对于参与重编程的这四个转录因子在细胞分化过程中所具有特定功能的理解。

刘小龙研究组的研究工作得到了国家自然科学基金委,科技部和上海市科委的经费支持。(生物谷Bioon.com) 

Downregulation of the transcription factor KLF4 is required for the lineage commitment of T cells

Xiaomin Wen, Haifeng Liu, Gang Xiao and Xiaolong Liu

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.

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