Posttranslational regulation on the synthesis and assembly of T cell receptor complexes by p56^<lck>.

大多数T淋巴细胞上表达的α-βT细胞抗原受体(TCR)是由至少6种不同的蛋白质(α、β、γ、Delta、epsilon和Zeta)组成的多亚单位跨膜复合体，它们组装在内质网(ER)中，然后转运到质膜。TCR复合体的表达在T细胞发育过程中是定量调节的，未成熟的CD4^+CD8^+胸腺细胞仅表达成熟T细胞表面α-βTCR复合体的10%。然而，在发育中的Alphabeta T细胞中低表达TCR的分子基础尚不清楚。在本研究中，我们报告了一项意想不到的发现，即未成熟的CD4^+CD8^+胸腺细胞与其成熟的T细胞后代相比，新生的组件链组装成完整的TCRalphabeta复合体受到严重损害。特别是，TCRα与TCRβ蛋白的初始结合在成熟T细胞中相对有效，在未成熟的CD4^+CD8^+胸腺细胞中明显无效，即使是一对匹配的转基因TCRα和TCRβ蛋白也是如此。未成熟胸腺细胞中TCRAlphabeta异源二聚体的形成效率低下是由于未成熟胸腺细胞内质网中新生TCRα蛋白的独特不稳定性所致，新生TCRα蛋白在CD4^+CD8^+胸腺细胞中的中位存活时间仅为15分钟，而在成熟T细胞中为75分钟。因此，这些数据表明内质网中TCRα蛋白的稳定性是受发育调节的，并为未成熟和成熟T细胞上Alphabeta TCR表达的定量差异提供了分子基础。此外，这些结果提供了第一个受体复合体的例子，其表达在发育过程中受到受体组装的翻译后限制的定量调节。

The alphabeta T cell antigen receptor (TCR) that is expressed on most T lymphocytes is a multisubunit transmembrane complex composed of at least six different proteins (alpha, beta, gamma, delta, epsilon and zeta) that are assembled in the endoplasmic reticulum (ER) and then transported to the plasma membrane. Expression of the TCR complex is quantitatively regulated during T cell development, with immature CD4^+CD8^+ thymocytes expressing only 10% of the number of surfce alphabeta TCR complexes that are expressed on mature T cells. However, the molecular basis for low TCR expression in developing alphabeta T cells is unknown. In the present study we report the the unexpected finding that assembly of nascent component chains into complete TCRalphabeta complexes is severely impaired in immature CD4^+CD8^+ thymocytes relative to their mature T cell progeny. In particular, the initial association of TCR alpha with TCR beta proteins, which occurs relatively efficiently in mature T cells, is markedly inefficient in immature CD4^+CD8^+ thymocytes, even for a matched pair of transgenic TCR alpha and TCR beta proteins. Inefficient formation of TCRalphabeta heterodimers in immature CD4^+CD8^+ thymocytes was found to result from the unique instability of nascent TCR alpha proteins within the ER of immature CD4^+CD8^+ thymocytes, with nascent TCR alpha proteins having a median survival time of only 15 min in CD4^+CD8^+ thymocytes, but > 75 min in mature T cells. Thus, these data demonstrate that stability of TCR alpha proteins within the ER is developmenally regulated and provide a molecular basis for quantitative differences in alphabeta TCR expression on immature and mature T cells. In addition, these results provide the first example of a receptor complex whose expression is quantitatively regulated during development by posttranslational limitations on receptor assembly.