Zhu J, Huang H, Guo L, Stonehouse T, Watson C J, Hu-Li J, Paul W E
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Exp Med. 2000 Oct 16;192(8):1125-34. doi: 10.1084/jem.192.8.1125.
Interleukin (IL)-4 and IL-12 together with T cell receptor (TCR) engagement are crucial for the differentiation of CD4(+) T cells into T helper (Th)2 or Th1 cells, respectively. Although IL-4 receptors (IL-4Rs) but not IL-12Rs are expressed on naive CD4(+) T cells, IL-4 has no apparent advantage over IL-12 in driving naive T cell differentiation when the cells are primed with both IL-4 and IL-12 in vitro. It was found that IL-4-induced phosphorylation of Janus kinases 1 and 3, IL-4R alpha, signal transducer and activator of transcription 6, and insulin receptor substrate 2 was strikingly but transiently inhibited by TCR ligation both in conventional and TCR transgenic T cells. TCR engagement also blocked the expression of an IL-4-inducible gene. Signals induced by other cytokines, including IL-2, IL-6, and interferon alpha, but not by insulin-like growth factor 1, were also blocked by TCR engagement. The capacity of various inhibitors to reverse TCR-mediated inhibition of IL-4 signaling suggested that activation of the Ras-mitogen-activated protein kinase pathway and of the calcineurin pathway contribute to desensitizing IL-4R. IL-4 responsiveness returned at about the time ( approximately 12 h) that IL-12-mediated signaling was first observed. Thus, through different mechanisms, neither IL-4R nor IL-12R has any clear advantage in polarizing cells; rather, the availability of cytokine is probably the limiting factor in this process.
白细胞介素（IL）-4和IL-12与T细胞受体（TCR）结合对于CD4(+) T细胞分别分化为辅助性T（Th）2或Th1细胞至关重要。尽管在初始CD4(+) T细胞上表达IL-4受体（IL-4Rs）而不表达IL-12受体，但当细胞在体外同时用IL-4和IL-12刺激时，IL-4在驱动初始T细胞分化方面相对于IL-12没有明显优势。研究发现，在传统T细胞和TCR转基因T细胞中，TCR连接均显著但短暂地抑制了IL-4诱导的Janus激酶1和3、IL-4Rα、信号转导子和转录激活子6以及胰岛素受体底物2的磷酸化。TCR结合还阻断了IL-4诱导基因的表达。其他细胞因子（包括IL-2、IL-6和干扰素α）诱导的信号，但胰岛素样生长因子1诱导的信号除外，也被TCR结合所阻断。各种抑制剂逆转TCR介导的IL-4信号抑制的能力表明，Ras-丝裂原活化蛋白激酶途径和钙调神经磷酸酶途径的激活有助于使IL-4R脱敏。IL-4反应性大约在首次观察到IL-12介导的信号传导时（约12小时）恢复。因此，通过不同机制，IL-4R和IL-12R在使细胞极化方面均无明显优势；相反，细胞因子的可用性可能是这一过程中的限制因素。
