The Journal of Experimental Medicine
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Published online 16 October 2000.
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© The Rockefeller University Press, 0022-1007/2000/10/1115/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 8, October 16, 2000 1115-1124

Original Article

Regulation of Cytokine Signaling by B Cell Antigen Receptor and Cd40-Controlled Expression of Heparan Sulfate Proteoglycans

Robbert van der Voorta, Robert M.J. Keehnena, Esther A. Beulinga, Marcel Spaargarena, and Steven T. Palsa

a Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
Department of Pathology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.31-20-696038931-20-566-5635

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-1{alpha} 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.

Key Words: proteoglycans • B lymphocytes • hepatocyte growth factor • CD44 • signaling

R. van der Voort's present address is Department of Tumor Immunology, University Medical Center St. Radboud, 6525 EX Nijmegen, The Netherlands.

Abbreviations used in this paper: BCR, B cell antigen receptor; CD44s, CD44 standard isoform; CXCR, CXC chemokine receptor; FGF, fibroblast growth factor; Gab1, Grb2-associated binder 1; GAG, glycosaminoglycan; GC, germinal center; HGF, hepatocyte growth factor; HS, heparan sulfate; HSPG, HS proteoglycan; PKB, protein kinase B; SAC, Staphylococcus aureus Cowan strain I; SDF, stromal cell-derived factor.

© 2000 The Rockefeller University Press


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