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Paracrine regulation of germinal center B cell adhesion through the c-met-hepatocyte growth factor/scatter factor pathway.

van der Voort R, Taher TE, Keehnen RM, Smit L, Groenink M, Pals ST - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

ABSTRACT
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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c-Met expression in the human tonsil. (A) Immunohistochemical double-staining for c-Met (blue) and IgD (red). c-Met is expressed by GC  cells and by vascular endothelium (arrows). Prominant IgD expression is present on B cells of the mantle zones. (B) Serial section of A, stained for c-Met  (blue) and CD38 (red). There are virtually no single c-Met–positive (blue) lymphocytes. Part of the GC cell show double staining (pink) (most clearly visible in the GC at the lower-right of the picture). A and B are not counterstained. (C) Immunohistochemical single-staining for DRC-1 (red) showing the  FDC-network of the GC. The FDC poor area at the left handside represents the GC-darkzone (dz). (D) serial section of C, stained for c-Met (red).  c-Met–positive cells are predominantly present in the GC-darkzone. C and D are counterstained with hematoxylin (blue).
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Figure 4: c-Met expression in the human tonsil. (A) Immunohistochemical double-staining for c-Met (blue) and IgD (red). c-Met is expressed by GC cells and by vascular endothelium (arrows). Prominant IgD expression is present on B cells of the mantle zones. (B) Serial section of A, stained for c-Met (blue) and CD38 (red). There are virtually no single c-Met–positive (blue) lymphocytes. Part of the GC cell show double staining (pink) (most clearly visible in the GC at the lower-right of the picture). A and B are not counterstained. (C) Immunohistochemical single-staining for DRC-1 (red) showing the FDC-network of the GC. The FDC poor area at the left handside represents the GC-darkzone (dz). (D) serial section of C, stained for c-Met (red). c-Met–positive cells are predominantly present in the GC-darkzone. C and D are counterstained with hematoxylin (blue).

Mentions: To investigate whether c-Met induction is a physiological phenomenon, that occurs also during antigen-specific B cell differentiation in vivo, we assessed the expression of c-Met on human tonsillar B cell subsets using FACS® triple staining. The subsets studied, recently defined by Pascual et al. (13), were: the naive B cell subset, IgD+CD38− (Bm1-2); two GC B cell subsets, IgD−CD38+CD77+ centroblasts (Bm3), and IgD−CD38+CD77− centrocytes (Bm4); and an IgD−CD38− memory B cell subset (Bm5). Fig. 3 shows that c-Met is expressed by CD38+CD77+ centroblasts (Bm3) and by a part of the CD38+CD77− subset. This finding is supported by immunohistochemical studies on frozen sections of human tonsillar tissue: as is shown in Fig. 4, c-Met is predominantly expressed by lymphocytes within the dark zone of the GC, which contains rapidly dividing centroblasts and low numbers of FDC. These results mean that c-Met induction in vivo, occurs in GC-cells at a pre-selection stage, i.e., cells that have recently been recruited by antigen plus antigen-specific T lymphocytes in the T cell– rich extrafollicular microenvironment.


Paracrine regulation of germinal center B cell adhesion through the c-met-hepatocyte growth factor/scatter factor pathway.

van der Voort R, Taher TE, Keehnen RM, Smit L, Groenink M, Pals ST - J. Exp. Med. (1997)

c-Met expression in the human tonsil. (A) Immunohistochemical double-staining for c-Met (blue) and IgD (red). c-Met is expressed by GC  cells and by vascular endothelium (arrows). Prominant IgD expression is present on B cells of the mantle zones. (B) Serial section of A, stained for c-Met  (blue) and CD38 (red). There are virtually no single c-Met–positive (blue) lymphocytes. Part of the GC cell show double staining (pink) (most clearly visible in the GC at the lower-right of the picture). A and B are not counterstained. (C) Immunohistochemical single-staining for DRC-1 (red) showing the  FDC-network of the GC. The FDC poor area at the left handside represents the GC-darkzone (dz). (D) serial section of C, stained for c-Met (red).  c-Met–positive cells are predominantly present in the GC-darkzone. C and D are counterstained with hematoxylin (blue).
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Related In: Results  -  Collection

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Figure 4: c-Met expression in the human tonsil. (A) Immunohistochemical double-staining for c-Met (blue) and IgD (red). c-Met is expressed by GC cells and by vascular endothelium (arrows). Prominant IgD expression is present on B cells of the mantle zones. (B) Serial section of A, stained for c-Met (blue) and CD38 (red). There are virtually no single c-Met–positive (blue) lymphocytes. Part of the GC cell show double staining (pink) (most clearly visible in the GC at the lower-right of the picture). A and B are not counterstained. (C) Immunohistochemical single-staining for DRC-1 (red) showing the FDC-network of the GC. The FDC poor area at the left handside represents the GC-darkzone (dz). (D) serial section of C, stained for c-Met (red). c-Met–positive cells are predominantly present in the GC-darkzone. C and D are counterstained with hematoxylin (blue).
Mentions: To investigate whether c-Met induction is a physiological phenomenon, that occurs also during antigen-specific B cell differentiation in vivo, we assessed the expression of c-Met on human tonsillar B cell subsets using FACS® triple staining. The subsets studied, recently defined by Pascual et al. (13), were: the naive B cell subset, IgD+CD38− (Bm1-2); two GC B cell subsets, IgD−CD38+CD77+ centroblasts (Bm3), and IgD−CD38+CD77− centrocytes (Bm4); and an IgD−CD38− memory B cell subset (Bm5). Fig. 3 shows that c-Met is expressed by CD38+CD77+ centroblasts (Bm3) and by a part of the CD38+CD77− subset. This finding is supported by immunohistochemical studies on frozen sections of human tonsillar tissue: as is shown in Fig. 4, c-Met is predominantly expressed by lymphocytes within the dark zone of the GC, which contains rapidly dividing centroblasts and low numbers of FDC. These results mean that c-Met induction in vivo, occurs in GC-cells at a pre-selection stage, i.e., cells that have recently been recruited by antigen plus antigen-specific T lymphocytes in the T cell– rich extrafollicular microenvironment.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus