The role of hepatocyte growth factor and its receptor c-met in interactions between lymphocytes and stromal cells in secondary human lymphoid organs

Secondary lymphoid tissue consists of two major populations of cells: lymph oid cells and stromal cells. It is generally accepted that these two cell p opulations influence each other however, factors mediating these processes are poorly understood. In this paper we characterize one of the possible me ans of communication between stroma and lymphocytes namely through hepatocy te growth factor/c-met receptor interactions. Hepatocyte growth factor (HGF ) is a pleiotropic factor that is mainly produced by mesenchymal cells and acts on cells of epithelial origin which express the HGF receptor c-met. He re we demonstrate that biologically active HGF is constitutively produced b y fibroblast-like stromal cells from human lymphoid tissues. HGF secretion from stromal cells was increased by direct contact with activated T cells. This increase was abrogated when activated T cells were separated physicall y from stromal cells. Using neutralizing antibody or cytokine inhibitors we provide evidence that enhancement of HGF production was due to additive ef fects of T-cell membrane-associated interleukin-1 (IL-1) and CD40 ligand. F inally, we also show that B lymphocytes activated with CD40L/anti-mu or pho rbol 12-myristate 13-acetate (PMA) express c-met receptor. Co-culture of ac tivated B cells with stromal cells from spleen leads to enhanced production of immunoglobulins. This can be partially inhibited by introduction of ant i-HGF neutralizing antibodies to the culture system. Substitution of stroma l cells with recombinant HGF did not produce enhancement of immunoglobulin secretion. On the other hand stimulation of c-met receptor with HGF leads t o enhanced integrin-mediated adhesion of activated B cells to vascular cell adhesion molecule (VCAM-1) and fibronectin. On the basis of the above expe riments we conclude that HGF production by fibroblast-like stromal cells ca n be modulated by activated T cells, thus providing signals for the regulat ion of adhesion of c-met expressing B cells to extracellular matrix protein s. In this way HGF may indirectly influence immunoglobulin secretion by B c ells.