INTRACELLULAR SIGNALS CONTROLLING LYMPHOCYTE DEVELOPMENT AND FUNCTION

目前还不清楚TCR及其辅助受体信号是如何控制淋巴细胞发育和分化的细胞内调节。我们以前证明，衔接分子Cbl参与组织胸腺细胞中的TCR信号，其缺陷导致体内增强的CD 4+胸腺细胞发育。使用基因敲除（ko）小鼠，我们现在证明，Cbl-b，Cbl家族蛋白的成员，是建立CD 28依赖性T细胞活化所必需的，并且在没有Cbl-b的情况下，小鼠变得高度容易诱导自身免疫性疾病。进一步的生物化学分析表明，Vav信号通路在突变T细胞中显著增强，表明Cbl-b通过抑制TCR信号激活Vav来调节CD 28依赖性。我们的研究结果首次表明，接头分子参与TCR及其辅助受体信号的协调，并进一步表明，Cbl-b和Vav信号通路的失调可能有助于人类自身免疫性疾病的发展。

It remains unclear how are TCR and its co-receptor signals controlling lymphocyte development and differentiation regulated intracellularly. We previously demonstrated that adaptor molecule Cbl is involved in organizing TCR signals in thymocytes, and its deficiency leads to an enhanced CD4+ thymocyte development in vivo. Using gene knock-out (ko) mice, we now demonstrate that Cbl-b, a member of Cbl family proteins, is required for the establishment of CD28 dependence of T cell activation, and that in the absence of Cbl-b mice become highly susceptible to the induction of autoimmune diseases. Further biochemistry analysis indicates that the Vav signaling pathway is significantly enhanced in the mutant T cells, suggesting that Cbl-b regulates the CD28 dependence through inhibiting Vav activation by TCR signals. Our results for the first time show that an adaptor molecule is involved in the coordination of TCR and its co-receptor signaling, and suggest further that dysregulation of Cbl-b and Vav signaling pathways might contribute to the development of autoimmune diseases in humans.