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By
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.
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