A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production
A role of suppressor of cytokine signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated interleukin 2 production
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DOI：
10.1084/jem.20020939
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发表时间：
2003-02-17
影响因子：
15.3
通讯作者：
Kubo, M
中科院分区：
文献类型：
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作者：
Matsumoto, A;Seki, Y;Kubo, M
细胞因子信号转导抑制因子（SOCS）3是一种负反馈调节因子，参与了酪氨酸介导的Janus激酶信号转导和转录激活因子信号转导。然而，这项研究表明，从转基因小鼠表达SOCS 3的T细胞表现出显着减少白细胞介素（IL）-2的生产诱导T细胞受体交联时，T细胞与CD 28共刺激。SOCS 3（+/-）小鼠中蛋白表达的降低增强了CD 28介导的IL-2产生，清楚地表明SOCS 3表达水平与IL-2产生能力之间的相关性。SOCS 3蛋白通过其SH 2结构域而不是激酶抑制区与磷酸化的CD 28相互作用。此外，SOCS 3 SH 2结构域中的点突变减弱了IL-2启动子激活中CD 28功能的抑制。与Th 1细胞中的干扰素γ和IL-2的产生相比，定向辅助性T细胞（Th）2只表达SOCS 3，并且Th 2细胞因子（如IL-4和IL-5）的产生对CD 28共刺激的依赖性要小得多。与这一观点一致，SOCS 3在早期T细胞活化中的表达水平影响由CD 28共刺激诱导的IL-2产生的能力。因此，SOCS 3可能在抑制CD 28介导的IL-2产生的过度进展中发挥替代作用。
Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3(+/-) mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon gamma and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production.