Abraham K M, Levin S D, Marth J D, Forbush K A, Perlmutter R M
Howard Hughes Medical Institute, University of Washington, Seattle 98195.
J Exp Med. 1991 Jun 1;173(6):1421-32. doi: 10.1084/jem.173.6.1421.
Accumulating evidence supports the contention that CD4 and CD8 receptor molecules play a critical signaling role during thymocyte development. The lymphocyte-specific protein tyrosine kinase (p56lck), by virtue of its physical association with these surface components, provides a likely candidate for the biochemical signal transducing element required for these effects. To investigate the function of p56lck in T lymphocytes, transgenic mice were produced that carry either the wild-type lck gene or a mutated lck gene encoding a constitutively activated form of p56lck (p56lckF505). Both transgenes were expressed in thymocytes under the control of the lck proximal promoter element. A large set of founder animals was obtained in which steady-state accumulation of lck transgene mRNA directly correlated with transgene copy number, suggesting that this transgene contains a dominant control region. Progeny of these founders exhibited a transgene-dependent dose-related decrease in the production of thymocytes bearing functional antigen receptors. This effect was strictly dependent on p56lck activity, in that both wild-type and mutated versions of the genes induced similar effects with differing efficiencies. Remarkably, even a twofold increase in p56lck abundance was sufficient to substantially disrupt the appearance of functional thymocytes. These results indicate that thymocyte maturation is regulated in part by signals derived from p56lck.
越来越多的证据支持这样一种观点，即CD4和CD8受体分子在胸腺细胞发育过程中发挥关键的信号传导作用。淋巴细胞特异性蛋白酪氨酸激酶（p56lck）由于与这些表面成分存在物理关联，成为这些效应所需生化信号转导元件的一个可能候选者。为了研究p56lck在T淋巴细胞中的功能，构建了转基因小鼠，它们携带野生型lck基因或编码组成型激活形式的p56lck（p56lckF505）的突变lck基因。两个转基因均在lck近端启动子元件的控制下在胸腺细胞中表达。获得了大量的奠基动物，其中lck转基因mRNA的稳态积累与转基因拷贝数直接相关，这表明该转基因含有一个显性控制区。这些奠基动物的后代表现出转基因依赖性的、与剂量相关的功能性抗原受体胸腺细胞产生减少。这种效应严格依赖于p56lck活性，因为基因的野生型和突变型版本以不同效率诱导相似的效应。值得注意的是，即使p56lck丰度增加两倍也足以显著破坏功能性胸腺细胞的出现。这些结果表明，胸腺细胞成熟部分受p56lck衍生信号的调节。
