Regulation of cytokine signaling by B cell antigen receptor and CD40-controlled expression of heparan sulfate proteoglycans

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 connect ive tissues. As a large number of cytokines involved in lymphoid tissue hom eostasis or inflammation contain potential HS-binding domains, HSPGs presum ably 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 rec eptor (BCR) and/or CD-CO 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-me diated B cell adhesion and migration. This interaction with HGF is highly s elective since the HSPGs did not bind the chemokine stromal cell-derived fa ctor (SDF)-1 alpha, even though the affinities of HGF and SDF-1 alpha for h eparin are similar. On the activated B cells, we observed induction of a sp ecific HSPG isoform of CD44 (CD44-HS), but not of other HSPGs such as synde cans or glypican-1. Interestingly, the expression of CD44-HS on B cells str ongly promotes HGF-induced signaling, resulting in an MS-dependent enhanced phosphorylation of Met, the receptor tyrosine kinase for HGF, as well as d ownstream 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 f unctional coreceptors that selectively promote cytokine signaling in B cell s, suggesting a dynamic role for HSPGs in antigen-specific B cell different iation.