Constitutive Notch signalling promotes CD4-CD8- thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals
Constitutive Notch signalling promotes CD4-CD8- thymocyte differentiation in the absence of the pre-TCR complex, by mimicking pre-TCR signals
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DOI：
10.1093/intimm/dxm113
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发表时间：
2007-12-01
影响因子：
4.4
通讯作者：
Izon, David J.
中科院分区：
文献类型：
--
作者：
Michie, Alison M.;Chan, Angela C.;Izon, David J.
Notch 1信号传导对于多能淋巴细胞前体向α β T细胞谱系的定向是必不可少的，并且在调节CD 4（-）CD 8（-）双阴性（DN）胸腺细胞中的β选择中起重要作用。然而，Notch在促进CD 4（+）CD 8（+）双阳性（DP）胸腺细胞发育中所起的作用尚不清楚。在这里，我们证明了一个组成型活性的Notch 1（ICN 1）结构引入RAG（-/-）淋巴细胞前体导致在体外T细胞培养系统中产生DP胸腺细胞。值得注意的是，发育拯救不仅依赖于完整Notch 1 RAM结构域的存在，而且依赖于Delta样信号，因为在完整胸腺或OP 9-DL 1共培养物中，但在OP 9-对照共培养物中，RAG（-/-）胸腺细胞中ICN 1诱导的DP发育发生。有趣的是，SLP-76（-/-）前体中的ICN 1表达仅导致对未成熟CD 8（+）单阳性阶段的最小发育拯救，表明Notch利用与前TCR复合物相同的信号传导途径。为了支持这一点，ICN 1的引入导致RAG（-/-）胸腺细胞中ERK-MAPK信号级联的激活。总之，这些研究表明，组成型Notch信号传导可以通过在T细胞促进环境中诱导前TCR样信号来绕过早期T细胞发育期间的β选择。
Notch1 signalling is essential for the commitment of multipotent lymphocyte precursors towards the alpha beta T-cell lineage and plays an important role in regulating beta-selection in CD4(-)CD8(-) double-negative (DN) thymocytes. However, the role played by Notch in promoting the development of CD4(+)CD8(+) double-positive (DP) thymocytes is poorly characterized. Here, we demonstrate that the introduction of a constitutively active Notch1 (ICN1) construct into RAG(-/-) lymphocyte precursors resulted in the generation of DP thymocytes in in vitro T-cell culture systems. Notably, developmental rescue was dependent not only on the presence of an intact Notch1 RAM domain but also on Delta-like signals, as ICN1-induced DP development in RAG(-/-) thymocytes occurred within an intact thymus or in OP9-DL1 co-cultures, but not in OP9-control co-cultures. Interestingly, ICN1 expression in SLP-76(-/-) precursors resulted in only a minimal developmental rescue to the immature CD8(+) single-positive stage, suggesting that Notch is utilizing the same signalling pathway as the pre-TCR complex. In support of this, ICN1 introduction resulted in the activation of the ERK-MAPK-signalling cascade in RAG(-/-) thymocytes. Taken together, these studies demonstrate that constitutive Notch signalling can bypass beta-selection during early T-cell development by inducing pre-TCR-like signals within a T-cell-promoting environment.