Huang Fang, Gu Hua
Fudan Medical School, Fudan University, Shanghai, China.
Immunol Rev. 2008 Aug;224:229-38. doi: 10.1111/j.1600-065X.2008.00655.x.
Negative regulation of intracellular signaling delivered by the antigen receptors and coreceptors plays an important role in lymphocyte development and activation. Recent data from our laboratory and others have identified the Cbl family of ubiquitin ligases as important negative regulators in both T-cell and B-cell antigen receptor and coreceptor signaling. We show that c-Cbl and Cbl-b, two members of the Cbl family of proteins, play a redundant role in establishing the major histocompatibility complex-dependent development of thymocytes and in thymic selection. They also control the activation threshold and CD28 costimulatory signaling in peripheral T cells. In B cells, c-Cbl and Cbl-b set the B-cell receptor signaling threshold critical for proper B-cell maturation and anergy induction. Biochemical studies indicate that the immune regulation by Cbl proteins correlate with their ubiquitin ligase function. Inactivation of Cbl-b also renders mice resistant to both transplanted and spontaneous tumors due to an enhanced anti-tumor immunity of CD8(+) T cells. These findings thus place Cbl proteins at the center of a complex immune network regulation and suggest that modulation of this signaling pathway may be beneficiary to the treatment of autoimmunity and cancer.
抗原受体和共受体传递的细胞内信号的负调控在淋巴细胞发育和激活中起重要作用。我们实验室及其他机构最近的数据已确定泛素连接酶的Cbl家族是T细胞和B细胞抗原受体及共受体信号传导中的重要负调控因子。我们发现，Cbl家族蛋白的两个成员c-Cbl和Cbl-b在建立主要组织相容性复合体依赖性胸腺细胞发育及胸腺选择中发挥冗余作用。它们还控制外周T细胞的激活阈值和CD28共刺激信号传导。在B细胞中，c-Cbl和Cbl-b设定了对B细胞正常成熟和无能诱导至关重要的B细胞受体信号阈值。生化研究表明，Cbl蛋白的免疫调节与其泛素连接酶功能相关。由于CD8(+) T细胞抗肿瘤免疫力增强，Cbl-b失活还使小鼠对移植性肿瘤和自发性肿瘤均具有抗性。因此，这些发现使Cbl蛋白处于复杂免疫网络调节的中心位置，并表明调节该信号通路可能有益于自身免疫性疾病和癌症的治疗。
