INTRACELLULAR SIGNALS CONTROLLING LYMPHOCYTE DEVELOPMENT AND FUNCTION

目前尚不清楚TCR及其辅助受体信号是如何在细胞内调控淋巴细胞发育和分化的。我们之前已经证明，接头分子Cbl参与了胸腺细胞TCR信号的组织，它的缺失导致了体内CD4胸腺细胞发育的增强。利用基因敲除(KO)小鼠，我们现在证明了Cbl家族蛋白Cbl-b是建立CD28依赖的T细胞激活所必需的，并且在缺乏Cbl-b的情况下，小鼠变得对诱导自身免疫性疾病高度敏感。进一步的生化分析表明，Vav信号通路在突变的T细胞中显著增强，提示Cbl-b通过抑制TCR信号对Vav的激活来调节CD28依赖。我们的结果首次表明，一个接头分子参与了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在人类自身免疫性疾病的发生发展中起作用。

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.