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© The Rockefeller University Press, 0022-1007/1997/6/2121/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 12, June 16, 1997 2121-2131

Articles

Paracrine Regulation of Germinal Center B Cell Adhesion through the c-Met–Hepatocyte Growth Factor/Scatter Factor Pathway

Robbert van der Voort, Taher E.I. Taher, Robert M.J. Keehnen, Lia Smit, Martijn Groenink, and Steven T. Pals

From the Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

T cell–dependent humoral immune responses are initiated by the activation of naive B cells in the T cell areas of the secondary lymphoid tissues. This primary B cell activation leads to migration of germinal center (GC) cell precursors into B cell follicles where they engage follicular dendritic cells (FDC) and T cells, and differentiate into memory B cells or plasma cells. Both B cell migration and interaction with FDC critically depend on integrin-mediated adhesion. To date, the physiological regulators of this adhesion were unkown. In the present report, we have identified the c-met–encoded receptor tyrosine kinase and its ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF), as a novel paracrine signaling pathway regulating B cell adhesion. We observed that c-Met is predominantly expressed on CD38+CD77+ tonsillar B cells localized in the dark zone of the GC (centroblasts). On tonsil B cells, ligation of CD40 by CD40-ligand, induces a transient strong upregulation of expression of the c-Met tyrosine kinase. Stimulation of c-Met with HGF/SF leads to receptor phosphorylation and, in addition, to enhanced integrin-mediated adhesion of B cells to both VCAM-1 and fibronectin. Importantly, the c-Met ligand HGF/SF is produced at high levels by tonsillar stromal cells thus providing signals for the regulation of adhesion and migration within the lymphoid microenvironment.

Address correspondence to Steven T. Pals, Department of Pathology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.

1Abbreviations used in this paper: BCR, B cell antigen receptor; CD40L, CD40 ligand; ECM, extracellular matrix; FDC, follicular dendritic cells; GC, germinal center; HGF/SF, hepatocyte growth factor/scatter factor; PKC, protein kinase C; SAC, Staphylococcus aureus Cowans strain; VCAM-1, vascular cell adhesion molecule 1.


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