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

在大多数T淋巴细胞上表达的α T细胞抗原受体（TCR）是由至少六种不同蛋白质（α、β、γ、δ、β和ζ）组成的多亚基跨膜复合物，所述蛋白质在内质网（ER）中组装，然后转运至质膜。TCR复合物的表达在T细胞发育过程中受到定量调节，未成熟的CD 4 ^+ CD 8 ^+胸腺细胞表达的表面α TCR复合物数量仅为成熟T细胞表达的10%。然而，在发育中的α-T细胞中低TCR表达的分子基础是未知的。在本研究中，我们报告了一个意想不到的发现，即相对于成熟T细胞后代，未成熟的CD 4 ^+ CD 8 ^+胸腺细胞中新生组分链组装成完整的TCR α复合物的能力严重受损。特别是，TCR α和TCR β蛋白的初始结合在成熟T细胞中相对有效，但在未成熟的CD 4 ^+ CD 8 ^+胸腺细胞中明显无效，即使是一对匹配的转基因TCR α和TCR β蛋白。未成熟的CD 4 ^+ CD 8 ^+胸腺细胞中TCR α异源二聚体的形成效率低下，这是由于未成熟的CD 4 ^+ CD 8 ^+胸腺细胞内质网内新生TCR α蛋白的独特不稳定性造成的，新生TCR α蛋白在CD 4 ^+ CD 8 ^+胸腺细胞中的中位存活时间仅为15分钟，而在成熟T细胞中的中位存活时间超过75分钟。因此，这些数据表明ER内TCR α蛋白的稳定性是发育调节的，并为未成熟和成熟T细胞上α 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例子的受体复合物的表达是定量调节在发展过程中的翻译后限制受体组装。

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.