Developmental progression of fetal HEB-/- precursors to the pre-T-cell stage is restored by HEBAlt
Developmental progression of fetal HEB-/- precursors to the pre-T-cell stage is restored by HEBAlt
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DOI：
10.1002/eji.201040360
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Anderson, Michele K.
中科院分区：
文献类型：
--
作者：
Braunstein, Marsela;Anderson, Michele K.
基因敲除研究表明，E蛋白转录因子HEB是正常胸腺细胞发育所必需的。我们已经确定了一种独特的HEB形式，称为HEBAlt，它只在T细胞发育的早期阶段表达，而HEBCan在整个T细胞发育过程中表达。在这里，我们表明HEB-/-前体在T细胞发育的β-选择检查点受到抑制，这是由于pT α表达和CD 3 β功能受损，这两者都是前TCR信号传导所必需的。然而，HEBAlt在HEB-/-前体中的转基因表达上调了pT α，并允许胎儿胸腺细胞发育至CD 4（+）CD 8（+）阶段。此外，HEBAlt确实克服了HEB-/- Rag-1（-/-）胸腺细胞中的CD 3+信号传导缺陷。HEBAlt转基因不允许Rag-1（-/-）前体绕过β选择，表明它不是其他E蛋白的显性负抑制剂。因此，我们的研究结果提供了第一个机制证据，表明HEBAlt在早期T细胞发育中起着关键作用，并表明它可以与胎儿胸腺基质成分合作，创造一个支持T细胞发育通过β-选择检查点的调节环境。
Gene knockout studies have shown that the E-protein transcription factor HEB is required for normal thymocyte development. We have identified a unique form of HEB, called HEBAlt, which is expressed only during the early stages of T-cell development, whereas HEBCan is expressed throughout T-cell development. Here, we show that HEB-/- precursors are inhibited at the beta-selection checkpoint of T-cell development due to impaired expression of pT alpha and function of CD3 epsilon, both of which are necessary for pre-TCR signaling. Transgenic expression of HEBAlt in HEB-/- precursors, however, upregulated pT alpha and allowed development to CD4(+)CD8(+) stage in fetal thymocytes. Moreover, HEBAlt did overcome the CD3 epsilon signaling defect in HEB-/- Rag-1(-/-) thymocytes. The HEBAlt transgene did not permit Rag-1(-/-) precursors to bypass beta-selection, indicating that it was not acting as a dominant negative inhibitor of other E-proteins. Therefore, our results provide the first mechanistic evidence that HEBAlt plays a critical role in early T-cell development and show that it can collaborate with fetal thymic stromal elements to create a regulatory environment that supports T-cell development past the beta-selection checkpoint.