Follicular Dendritic Cells Catalyze Hepatocyte Growth Factor (HGF) Activation in the Germinal Center Microenvironment by Secreting the Serine Protease HGF Activator

Abstract

Ag-specific B cell differentiation, the process that gives rise to plasma cells and memory B cells, involves the formation of germinal centers (GC). Within the GC microenvironment, multiple steps of B cell proliferation, selection, and maturation take place, which are controlled by the BCR in concert with cytokines and contact-dependent signals from follicular dendritic cells (FDCs) and T cells. Signaling by the multifunctional cytokine hepatocyte growth factor (HGF) and its receptor MET has been shown to induce integrin-mediated adhesion of B cells to VCAM-1, which is expressed by FDCs. In the present study we have examined the expression of regulatory components of the HGF/MET pathway, including HGF activator (HGFA), within the secondary lymphoid organ microenvironment. We show that MET is expressed by both centroblasts and plasma cells, and that HGFA is expressed by plasma cells. Because we have shown that HGF is a potent growth and survival factor for malignant plasma cells, HGF may also serve as a survival factor for normal plasma cells. Furthermore, we demonstrate that FDCs are the major source for HGF and its activator within the GC microenvironment. Both HGF and HGFA are expressed by FDCs in the GC dark zone (CD21high/CD23low), but not in the light zone (CD21high/CD23high). These findings suggest that HGF and HGFA provided by dark zone FDCs help to regulate the proliferation, survival, and/or adhesion of MET-positive centroblasts.

Establishment of Lymphotoxin β Receptor Signaling-Dependent Cell Lines with Follicular Dendritic Cell Phenotypes from Mouse Lymph Nodes

“…In contrast, among the genes expressed at higher levels in our FDC-like lines compared with BMDCs (listed in Fig. 7B), those marked with asterisks have been shown to be expressed in FDC preparations described in previous reports from other laboratories (51)(52)(53). These included the genes of CXCL12, CXCL13, procollagen type Ia, biglycan, VCAM-1, C4, CXCL1, connective tissue growth factor, insulin-like growth factor-binding protein 3, secreted acidic cysteine-rich glycoprotein, and prostacyclin synthase, thus further confirming the FDC-like characters of pFL and FL-Y cells.…”

Molecular pathways in follicular lymphoma

“…79 FDCs also provide stimulatory molecules such as interleukin-15, 8D6 (CD320), BAFF and hepatocyte growth factor (HGF), which may all have a role in normal GC B-cell expansion and may exert a similar function in FL. [90][91][92][93][94][95] Production of tumor necrosis factor (TNF) by B cells is critically important for the generation of fully developed FDCs out of resident stromal cells upon p55-TNF-R signaling. [96][97][98] Moreover, sustained interaction of TNF and LTa 1 b 2 is important for the maintenance of mature FDCs networks.…”

miRNA profiling of B-cell subsets: specific miRNA profile for germinal center B cells with variation between centroblasts and centrocytes

“…29 B-cell subset RNA from three different tonsil samples were pooled together accordingly to rule out small differences related to genetic variation in individuals and differences related to histology. We used a commercially available miRNA quantitative RT-PCR (qRT-PCR) profiling kit (Applied Biosystems, Foster City, USA), which, at that time, contained 183 miRNAs.…”

“…29 Briefly, mononuclear cells were isolated by Ficoll-Isopaque density gradient centrifugation. The collected cell suspension was stained with FITC-conjugated anti-human IgD, PE-conjugated anti-human CD19 (both from Dako, Glostrup, Denmark) and allophycocyanin-conjugated anti-human CD38 (BD Pharmingen, NJ, USA).…”