Abstract
Intercellular channels called gap junctions enable multicellular organisms to exchange information rapidly between cells. Though gap junctions are held to be ubiquitous in solid tissues, we have only recently found them in the lymphoid organs. Functional direct cell-cell communication has now been confirmed by us and other groups in bone marrow, thymus, and in secondary lymphoid tissues. What functions do they serve in the lymphoreticular system where, so far, only cytokines/growth factors and adhesion molecules have been considered as regulators? Here we show evidence for and refer to published work about functional direct cellcell communication through gap junctions in germinal center reactions and make proposals for their role in the immune response. We found a large amount of the connexin43 (Cx43) gap junctions in the germinal centers of secondary lymphoid follicles. Ultrastructurally and immunohistologically, most of the junctions were detected on the processes of follicular dendritic cells (FDC) enveloping nondividing centrocytes in the light zone of germinal centers where B-cell selection is thought to take place. Further support for this finding came by revealing the Cx43 mRNA in situ at the same location as the protein. On antigen challenge, gap junctions appeared on the FDC as they formed meshworks in germinal centers. In order to find out which germinal center cells communicate directly, we separated FDC-rich, low-density, B-cell fractions from human tonsil. In culture, we injected single FDC with the low-molecular-weight fluorescent dye, Lucifer Yellow (Mr 457 Da), which passed between adjacent FDC and sometimes from FDC to B cells. Based on these findings and their assigned functions in other tissues, gap junctions may contribute to germinal center reactions in the following ways: (1) they may regulate follicle pattern formation by controlling FDC growth, (2) they may be involved in FDC-B-cell signaling contributing to the final rescue of selected B cells from apoptosis, and (3) they may enable FDC to work as a functional syncytium providing a cellular internet for integrating germinal center events. Data supporting these interpretations are briefly discussed.
Highlights
T-cell-dependent antigen response is held to be regulated by receptor-ligand interactions such as those among antigen, antibody, cytokines, or adhesion molecules and their cell-membrane receptors
Gap junctions are arranged along the processes of follicular dendritic cells (FDC) that envelope nondividing centrocytes
Mice immunization experiments confirm that developing FDC produce gradually increasing numbers of gap junctions up to the formation of full secondary follicles (Krenacs et al, 1997)
Summary
T-cell-dependent antigen response is held to be regulated by receptor-ligand interactions such as those among antigen, antibody, cytokines, or adhesion molecules and their cell-membrane receptors (see Clark and Ledbetter, 1994; MacLennan, 1994; Thorbecke et al, 1994). Metabolic communication through gap junctions has been implicated in the regulation of cell growth and proliferation during tissue development (Loewenstein and Rose, 1992; Warner, 1992) and in the rapid propagation of local signals through coupled cell networks (reviewed by Bruzzone et al, 1996). Function is coordinated and which kinds of interaction take place between FDC and lymphocytes, in the light of our recent finding of direct intercellular communication through gap junctions in the lymphoid germinal center.
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