van der Voort R, Keehnen R M, Beuling E A, Spaargaren M, Pals S T
Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
J Exp Med. 2000 Oct 16;192(8):1115-24. doi: 10.1084/jem.192.8.1115.
Recently, biochemical, cell biological, and genetic studies have converged to reveal that integral membrane heparan sulfate proteoglycans (HSPGs) are critical regulators of growth and differentiation of epithelial and connective tissues. As a large number of cytokines involved in lymphoid tissue homeostasis or inflammation contain potential HS-binding domains, HSPGs presumably also play important roles in the regulation of the immune response. In this report, we explored the expression, regulation, and function of HSPGs on B lymphocytes. We demonstrate that activation of the B cell antigen receptor (BCR) and/or CD40 induces a strong transient expression of HSPGs on human tonsillar B cells. By means of these HSPGs, the activated B cells can bind hepatocyte growth factor (HGF), a cytokine that regulates integrin-mediated B cell adhesion and migration. This interaction with HGF is highly selective since the HSPGs did not bind the chemokine stromal cell-derived factor (SDF)-1 alpha, even though the affinities of HGF and SDF-1alpha for heparin are similar. On the activated B cells, we observed induction of a specific HSPG isoform of CD44 (CD44-HS), but not of other HSPGs such as syndecans or glypican-1. Interestingly, the expression of CD44-HS on B cells strongly promotes HGF-induced signaling, resulting in an HS-dependent enhanced phosphorylation of Met, the receptor tyrosine kinase for HGF, as well as downstream signaling molecules including Grb2-associated binder 1 (Gab1) and Akt/protein kinase B (PKB). Our results demonstrate that the BCR and CD40 control the expression of HSPGs, specifically CD44-HS. These HSPGs act as functional coreceptors that selectively promote cytokine signaling in B cells, suggesting a dynamic role for HSPGs in antigen-specific B cell differentiation.
最近，生物化学、细胞生物学和遗传学研究都表明，整合膜硫酸乙酰肝素蛋白聚糖（HSPGs）是上皮组织和结缔组织生长与分化的关键调节因子。由于大量参与淋巴组织稳态或炎症的细胞因子含有潜在的HS结合域，因此HSPGs可能在免疫反应调节中也发挥重要作用。在本报告中，我们探究了HSPGs在B淋巴细胞上的表达、调控及功能。我们证明，B细胞抗原受体（BCR）和/或CD40的激活会诱导人扁桃体B细胞上HSPGs的强烈瞬时表达。通过这些HSPGs，活化的B细胞能够结合肝细胞生长因子（HGF），这是一种调节整合素介导的B细胞黏附和迁移的细胞因子。这种与HGF的相互作用具有高度选择性，因为即使HGF和基质细胞衍生因子（SDF）-1α对肝素的亲和力相似，HSPGs也不结合趋化因子SDF-1α。在活化的B细胞上，我们观察到了CD44的一种特异性HSPG亚型（CD44-HS）的诱导表达，但未观察到其他HSPGs如syndecans或glypican-1的诱导表达。有趣的是，B细胞上CD44-HS的表达强烈促进HGF诱导的信号传导，导致HGF的受体酪氨酸激酶Met以及包括Grb2相关结合蛋白1（Gab1）和Akt/蛋白激酶B（PKB）在内的下游信号分子的HS依赖性磷酸化增强。我们的结果表明，BCR和CD40控制HSPGs的表达，特别是CD44-HS的表达。这些HSPGs作为功能性共受体，选择性地促进B细胞中的细胞因子信号传导，表明HSPGs在抗原特异性B细胞分化中发挥动态作用。
