Paracrine regulation of germinal center B cell adhesion through the c-met-hepatocyte growth factor/scatter factor pathway.
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.
van der Voort
R
R
Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Taher
T E
TE
Keehnen
R M
RM
Smit
L
L
Groenink
M
M
Pals
S T
ST
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002448:Cell Adhesion; D005353:Fibronectins / Q000502:physiology; D018858:Germinal Center / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D051379:Mice; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
D005353:Fibronectins; D019010:Vascular Cell Adhesion Molecule-1; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases