title: Regulation of cytokine signaling by B cell antigen receptor and CD40-controlled expression of heparan sulfate proteoglycans.
abstract: 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.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: van der Voort
authors.forename: R M
authors.initials: RM
authors.lastname: Keehnen
authors.forename: E A
authors.initials: EA
authors.lastname: Beuling
authors.forename: M
authors.initials: M
authors.lastname: Spaargaren
authors.forename: S T
authors.initials: ST
authors.lastname: Pals
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002051:Burkitt Lymphoma; D019013:CD40 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000493:pharmacokinetics / Q000494:pharmacology; D016207:Cytokines / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D019812:Heparan Sulfate Proteoglycans / Q000096:biosynthesis*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D014066:Palatine Tonsil / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017154:Stromal Cells / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D019013:CD40 Antigens; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016207:Cytokines; D019812:Heparan Sulfate Proteoglycans; D018960:Hyaluronan Receptors; D011947:Receptors, Antigen, B-Cell; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor