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

p56^<lck> 对 T 细胞受体复合物合成和组装的翻译后调节。

• 批准号: 05670295
• 负责人: NAKAYAMA Toshinori
• 金额: $ 1.34万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1994
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670295/
• 关键词: p56^<lck>; T cell receptor; CD4^+CD8^+ thymocytes; P56^<lCK>; T細胞抗原レセプター; 胸腺; 小胞体; CD4; ドミナント・ネガティブ

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.

在大多数T淋巴细胞上表达的α - T细胞抗原受体（TCR）是一种多亚基跨膜复合物，由至少六种不同的蛋白质（α, β, γ, δ， epsilon和zeta）组成，这些蛋白质在内质网（ER）中组装，然后运输到质膜。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CD4^+CD8^+胸腺细胞仅表达成熟T细胞表面α - TCR复合物数量的10%。然而，发育中的T细胞TCR低表达的分子基础尚不清楚。在本研究中，我们报告了一个意想不到的发现，在未成熟的CD4^+CD8^+胸腺细胞中，相对于成熟的T细胞后代，新生成分链组装成完整的tcrα -复合物严重受损。特别是，TCR α与TCR β蛋白的初始结合，在成熟的T细胞中相对有效地发生，在未成熟的CD4^+CD8^+胸腺细胞中明显低效，即使是配对的转基因TCR α和TCR β蛋白也是如此。未成熟CD4^+CD8^+胸腺细胞中TCR α蛋白的独特不稳定性导致未成熟CD4^+CD8^+胸腺细胞中TCR α蛋白的中位存活时间在CD4^+CD8^+胸腺细胞中仅为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内TCR α蛋白的稳定性受到发育调控，并为未成熟T细胞和成熟T细胞α - TCR表达的数量差异提供了分子基础。此外，这些结果提供了受体复合物的第一个例子，其表达在发育过程中受到翻译后受体组装限制的定量调节。

项目成果

Kearse, K.P.: "Developmental regulation of alphabeta T cell antigen receptor expression results from differential stability of nascent TCRalpha proteins within the endoplasmic reticulum of immature and mature T cells." EMBO Journal. 13. 4504-4514 (1994)

Kearse, K.P.：“alphabeta T 细胞抗原受体表达的发育调节是由未成熟和成熟 T 细胞内质网内新生 TCRalpha 蛋白的稳定性差异造成的。”

V.Reeders: "T cell development in the thymus.Handbook of Experimental Immunology.(5th ed.)" Blackwell Scientific Publications, (1994)

V.Reeders：“胸腺中的 T 细胞发育。实验免疫学手册。（第 5 版）”Blackwell Scientific Publications，（1994）

Shores,E.W.: "Structurally distinct T cell receptor complexes on developmentally distinct T cell population in severe combined immunodeficiency mice expressing a TCRβ transgene." J.Immunol.150. 1263-1275 (1993)

Shores，E.W.：“表达 TCRβ 转基因的严重联合免疫缺陷小鼠中发育不同的 T 细胞群的结构不同的 T 细胞受体复合物。”1263-1275 (1993)。

Nagasawa,T.: "Negative selection of thymus-dependent CD4^+8^+ intraepithelial lymphocytes by internal superantigens." Cell.Immunol.147. 158-166 (1993)

Nagasawa,T.：“内部超抗原对胸腺依赖性 CD4^8^ 上皮内淋巴细胞的负选择。”

Nakayama,T.: "Decreased signaling competence as a result of receptor overexpression:Overexpression of CD4 reduces its ability to activate P56lck tyrosine kinase and to regulate T-cell antigen receptor expression in immature CD4+CD8+thymocytes." Proc.Natl.

Nakayama,T.：“受体过度表达导致信号传导能力下降：CD4 过度表达会降低其激活 P56lck 酪氨酸激酶和调节未成熟 CD4 CD8 胸腺细胞中 T 细胞抗原受体表达的能力。”