Brunner M C, Chambers C A, Chan F K, Hanke J, Winoto A, Allison J P
Howard Hughes Medical Research Institute, Cancer Research Laboratory, Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA.
J Immunol. 1999 May 15;162(10):5813-20.
CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation.
单克隆抗体与CTLA-4结合会抑制T细胞活化时的白细胞介素-2（IL-2）产生和增殖，而CD28则会增强这一过程。在此，我们利用抗体交联分析了CTLA-4介导的对初始CD4+ T细胞T细胞活化抑制作用的相关机制。CTLA-4连接通过抑制IL-2转录来抑制CD3/CD28诱导的IL-2 mRNA积累，这似乎部分是通过减少细胞核中活化T细胞核因子（NF-AT）的积累来介导的。然而，CTLA-4连接似乎并不影响CD28介导的IL-2 mRNA稳定。此外，当用抗CD3/CD28和单独抗CD3刺激T细胞时，CTLA-4结合通过抑制细胞周期蛋白D3、细胞周期蛋白依赖性激酶（cdk）4和cdk6的产生来抑制细胞周期进程。这些结果表明，CTLA-4信号传导在IL-2转录以及细胞周期中不依赖IL-2的事件水平上抑制T细胞活化早期的事件，而不仅仅是对抗CD28介导的共刺激作用。
