Haxhinasto Sokol A, Bishop Gail A
Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242, USA.
J Immunol. 2003 Nov 1;171(9):4655-62. doi: 10.4049/jimmunol.171.9.4655.
Signaling by Ag to the B cell Ag receptor (BCR) is enhanced by several cooperating signals, including several provided by B-T cell interactions. One of these, CD40, provides critical signals for B cell differentiation, isotype switching, and B cell memory. The molecular mechanisms by which BCR and CD40 signals synergize are not well understood. Although the BCR and CD40 share certain signaling pathways, we hypothesized that unique signals provided by each could provide mutual enhancement of their signaling pathways. The BCR, but not CD40, activates protein kinase D (PKD), while CD40, but not the BCR, employs the TNFR-associated factor (TRAF) adapter proteins in signaling. In this study, we show that genetic or pharmacologic inhibition of BCR-mediated PKD activation in B lymphocytes abrogated the synergy between the CD40 and the BCR, as measured by activation of Ig and cytokine secretion. Interestingly, the role of PKD was dependent upon the association of CD40 with TRAF2, and was inhibited by the binding of TRAF3, revealing a novel functional link between these two classes of signaling molecules.
抗原（Ag）向B细胞抗原受体（BCR）发出的信号通过几种协同信号得到增强，其中包括B细胞与T细胞相互作用提供的几种信号。其中之一，CD40，为B细胞分化、同种型转换和B细胞记忆提供关键信号。BCR和CD40信号协同作用的分子机制尚不清楚。尽管BCR和CD40共享某些信号通路，但我们推测，各自提供的独特信号可能会相互增强它们的信号通路。BCR可激活蛋白激酶D（PKD），而CD40则不能；而CD40在信号传导中利用肿瘤坏死因子受体相关因子（TRAF）衔接蛋白，BCR则不能。在本研究中，我们发现，通过对Ig激活和细胞因子分泌的检测，B淋巴细胞中BCR介导的PKD激活的基因或药理学抑制消除了CD40和BCR之间的协同作用。有趣的是，PKD的作用取决于CD40与TRAF2的结合，并受到TRAF3结合的抑制，揭示了这两类信号分子之间的一种新的功能联系。
