King L B, Norvell A, Monroe J G
Department of Pathology and Laboratory Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA.
J Immunol. 1999 Mar 1;162(5):2655-62.
Signals transduced through the B cell Ag receptor (BCR) drive B cell development. However, BCR-induced responses are developmentally regulated; immature B cells are tolerized following antigenic exposure while mature B cells are triggered to proliferate and differentiate. This differential responsiveness allows for the negative selection of self-reactive immature B cells while simultaneously allowing for clonal expansion of mature B cells in response to foreign Ags. Intrinsic differences in BCR-induced signal transduction at various stages of development may account for this functional dichotomy. We had previously demonstrated that the BCR-induced proliferation of mature B cells is accompanied by an increase in intracellular calcium levels and polyphosphoinositide bis phosphate (PIP2) hydrolysis. In contrast, immature B cells that undergo BCR-induced apoptosis increase intracellular calcium in the relative absence of PIP2 hydrolysis. Since PIP2 hydrolysis leads to the generation of diacylglycerol, a cofactor for protein kinase C (PKC) activation, these data suggested that an "imbalance" in BCR-induced signal transduction resulting from a relative inability to activate PKC may play a role in the susceptibility of immature B cells to BCR-induced apoptosis. In support of this hypothesis, we demonstrate that PKC activation can rescue immature B cells from BCR-induced apoptosis. Furthermore, the susceptibility of immature B cells to BCR-induced apoptosis is recapitulated in mature B cells that are either PKC depleted or are stimulated in the presence of PKC inhibitors, suggesting that an uncoupling of PKC activation from BCR-induced signaling is responsible for the apoptotic response of immature B cells.
通过B细胞抗原受体（BCR）转导的信号驱动B细胞发育。然而，BCR诱导的反应受到发育调控；未成熟B细胞在接触抗原后会产生耐受性，而成熟B细胞则被触发增殖和分化。这种不同的反应性使得自身反应性未成熟B细胞能够进行阴性选择，同时允许成熟B细胞针对外来抗原进行克隆扩增。在发育的各个阶段，BCR诱导的信号转导的内在差异可能解释了这种功能二分法。我们之前已经证明，BCR诱导的成熟B细胞增殖伴随着细胞内钙水平的升高和多磷酸肌醇二磷酸（PIP2）的水解。相比之下，经历BCR诱导凋亡的未成熟B细胞在相对缺乏PIP2水解的情况下会增加细胞内钙。由于PIP2水解会导致二酰基甘油的产生，二酰基甘油是蛋白激酶C（PKC）激活的辅助因子，这些数据表明，由于相对无法激活PKC而导致的BCR诱导信号转导中的“失衡”可能在未成熟B细胞对BCR诱导凋亡的易感性中起作用。为支持这一假设，我们证明PKC激活可以挽救未成熟B细胞免受BCR诱导的凋亡。此外，在PKC缺失或在PKC抑制剂存在下受到刺激的成熟B细胞中，也再现了未成熟B细胞对BCR诱导凋亡的易感性，这表明PKC激活与BCR诱导信号转导的解偶联是未成熟B细胞凋亡反应的原因。
