Study of CDK inhibitors in B cell immune response

B淋巴细胞通过强抗原受体(BCR)交联而发生凋亡。然而，CD4O信号或CD72连接可阻断BCR介导的细胞凋亡，并诱导BCR连接的B细胞增殖。在B细胞系WEHI-231中，BCR结扎增加了CDK抑制物p27的水平。CDK抑制剂的诱导表达导致WEHI-231细胞死亡，提示CDK抑制剂参与了BCR介导的细胞凋亡。相反，在刺激上调CDK抑制剂时，成纤维细胞会经历细胞周期停滞，但不会发生凋亡。然而，这些刺激诱导过表达c-Myc的成纤维细胞发生凋亡。此前，c-Myc的结构性过表达被证明可以阻断BCR介导的WEHI-231细胞凋亡。通过诱导表达c-Myc，我们发现先前的结果是人为的，c-Myc的过表达增强了BCR介导的细胞凋亡。这些结果有力地表明，CDK抑制剂和c-Myc在B细胞的死亡和增殖调节中起重要作用。当B细胞在CD4O信号或CD72连接的情况下存活和增殖时，CDK抑制物p27的水平降低。我们发现CD72被Lyn磷酸化，并通过招募SHP-1负调控BCR信号。此外，Lyn还降低了c-Myc的表达水平。因此，CD72可以负性调节c-Myc和CDK抑制物，导致B细胞的存活和增殖。

B lymphocytes undergo apoptosis by strong antigen receptor (BCR) crosslinking. However, CD4O signaling or CD72 ligation abrogates BCR-mediated apoptosis and induces proliferation of BCR-ligated B cells. In the B cell line WEHI-231, BCR ligation increased the level of the CDK inhibitor p27. Inducible expression of CDK inhibitors caused cell death of WEHI-231, suggesting that CDK inhibitors are involved in BCR-mediated apoptosis. In contrast, fibroblasts undergo cell cycle arrest but not apoptosis upon stimulation up-regulating CDK inhibitors. However, those stimulations induce apoptosis in-fibroblasts overexpressing c-Myc. Previously, constitutive overexpression of c-Myc was shown to block BCR-mediated apoptosis in WEHI-231. By inducibly expressing c-Myc, we showed that the previous result is an artifact and that overexpression of c-Myc enhances BCR-mediated apoptosis. Those results strongly suggest that CDK inhibitors and c-Myc play an important role in the regulation of death as well as proliferation of B cells.When B cells survive and proliferate in the presence of CD4O signaling or CD72 ligation, the level of the CDK inhibitor p27 is reduced. We showed that CD72 is phosphorylated by Lyn and negatively regulates BCR signaling by recruiting SHP-1. Moreover, Lyn reduced the expression level of c-Myc. CD72 may thus negatively regulate c-Myc and CDK inhibitors, resulting in survival and proliferation of B cells.