Killeen N, Davis C B, Chu K, Crooks M E, Sawada S, Scarborough J D, Boyd K A, Stuart S G, Xu H, Littman D R
Department of Microbiology, University of California at San Francisco 94143-0414.
Philos Trans R Soc Lond B Biol Sci. 1993 Oct 29;342(1299):25-34. doi: 10.1098/rstb.1993.0131.
The ectodomains of the T cell surface glycoproteins CD4 and CD8 bind to membrane-proximal domains of MHC class II and class I molecules, respectively, while both cytoplasmic domains interact with the protein tyrosine kinase (PTK) p56lck (lck) through a shared cysteine-containing motif. Function of CD4 and CD8 requires their binding to the same MHC molecule as that recognized by the T cell antigen receptor (TCR). In vitro studies indicate that CD4-associated lck functions even in the absence of kinase activity. In vivo experiments show that, whereas helper T cell development is impaired in CD4-deficient mice, high level expression of a transgenic CD4 that cannot bind lck rescues development of this T cell subset. These studies suggest that CD4 is an adhesion molecule whose localization is regulated through protein-protein interactions of the associated PTK and whose function is to increase the stability of the TCR signalling complex by binding to the relevant MHC. The function of CD4 in development has been further studied in the context of how double positive (CD4+CD8+) thymocytes mature into either CD4+ T cells with helper function and TCR specificity for class II or into CD8+ T cells with cytotoxic function and specificity for class I. Studies using CD4-transgenic mice indicate that development of single positive T cells involves stochastic downregulation of either CD4 or CD8, coupled to activation of a cytotoxic or helper program, respectively, and subsequent selection based on the ability of the TCR and remaining co-receptor to engage the same MHC molecule.
T细胞表面糖蛋白CD4和CD8的胞外结构域分别与MHC II类和I类分子的膜近端结构域结合，而两者的胞质结构域都通过一个共享的含半胱氨酸基序与蛋白酪氨酸激酶（PTK）p56lck（lck）相互作用。CD4和CD8的功能需要它们与T细胞抗原受体（TCR）识别的同一MHC分子结合。体外研究表明，即使在没有激酶活性的情况下，与CD4相关的lck也能发挥作用。体内实验表明，虽然在CD4缺陷小鼠中辅助性T细胞的发育受损，但不能与lck结合的转基因CD4的高水平表达可挽救该T细胞亚群的发育。这些研究表明，CD4是一种黏附分子，其定位通过相关PTK的蛋白质-蛋白质相互作用来调节，其功能是通过与相关MHC结合来增加TCR信号复合物的稳定性。在双阳性（CD4+CD8+）胸腺细胞如何成熟为具有辅助功能且对II类具有TCR特异性的CD4+ T细胞或成熟为具有细胞毒性功能且对I类具有特异性的CD8+ T细胞的背景下，对CD4在发育中的功能进行了进一步研究。使用CD4转基因小鼠的研究表明，单阳性T细胞的发育涉及CD4或CD8的随机下调，分别与细胞毒性或辅助程序的激活相关，随后根据TCR和剩余共受体与同一MHC分子结合的能力进行选择。
