Durand Caylib A, Westendorf Jens, Tse Kathy W K, Gold Michael R
Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Eur J Immunol. 2006 Aug;36(8):2235-49. doi: 10.1002/eji.200535004.
The localization of B cells to lymphoid organs where they can become activated and differentiate into antibody-secreting plasma cells is controlled by multiple chemoattractants that promote cell migration and integrin-mediated adhesion. CXCL13 and sphingosine 1-phosphate (S1P) are two important chemoattractants that control the trafficking of B cells. CXCL13 directs B lymphocytes to lymphoid follicles where they receive survival signals and, if activated, undergo a germinal center response. In contrast, S1P allows B cells and plasma cells to exit lymphoid organs and re-enter the circulation. The Rap1 GTPase is a key regulator of cell adhesion and cell migration in a number of systems. We now show that Rap activation is required for CXCL13 and S1P to induce B cell migration as well as adhesion to ICAM-1 and VCAM-1. We also show that Pyk2, a tyrosine kinase involved in cytoskeleton rearrangements and B cell migration, is a downstream target of both CXCL13 and S1P signaling and that Rap activation is important for CXCL13 and S1P to stimulate tyrosine phosphorylation of Pyk2, a modification that increases Pyk2 kinase activity. This suggests that the ability of CXCL13 and S1P to direct the trafficking and localization of B cells in vivo may be dependent on Rap activation.
B细胞定位于淋巴器官，在那里它们可以被激活并分化为分泌抗体的浆细胞，这一过程受多种趋化因子控制，这些趋化因子促进细胞迁移以及整合素介导的黏附。CXCL13和1-磷酸鞘氨醇（S1P）是控制B细胞运输的两种重要趋化因子。CXCL13引导B淋巴细胞至淋巴滤泡，在那里它们接收存活信号，并且如果被激活，会经历生发中心反应。相反，S1P允许B细胞和浆细胞离开淋巴器官并重新进入循环。Rap1 GTP酶是许多系统中细胞黏附和细胞迁移的关键调节因子。我们现在表明，Rap激活是CXCL13和S1P诱导B细胞迁移以及黏附于细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）所必需的。我们还表明，参与细胞骨架重排和B细胞迁移的酪氨酸激酶Pyk2是CXCL13和S1P信号传导的下游靶点，并且Rap激活对于CXCL13和S1P刺激Pyk2的酪氨酸磷酸化很重要，这种修饰增加了Pyk2激酶活性。这表明CXCL13和S1P在体内引导B细胞运输和定位的能力可能依赖于Rap激活。
