112 T. KRENACS and M. ROSENDAAL memory B-cell production takes place (Krenacs and Rosendaal, 1995; Krenacs et al., 1997). Gap junctions consist of hundreds of small chan- nels (connexons) arranged into plaques in the cell membrane (Makowski et al., 1977). Connexons produced by adjacent cells are aligned and small molecules and ions (< 1 kDa) can be rapidly exchanged through them between the coupled cells. These may include small metabolites, morphogens, and second messengers like Ca+2 ions, cyclic-AMP, or 1,4,5-inositol-triphosphate (Saez et al., 1989; Granot and Dekel, 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). Members of the gap-junction multigene family can be traced in tissues immunohis- tologically by detecting connexin molecules, six of which form the connexon hemi-channel (Makowski et al., 1977; Kumar and Gilula, 1996). In germinal center reactions, combinations of the antigen, T-cell cytokines, growth factors, and adhesion molecules are implicated in the activation, rescue, selection, and isotype switching of B lympho- cytes. As a result, plasma and memory B cells are formed in a highly controlled manner against the antigen (Clark and Ledbetter, 1994; MacLennan, 1994; Thorbecke et al., 1994). Considering their individual complexity, it is not clear how these multifactorial events are so integrated that the whole immune response seems strictly organized both structurally and functionally. It has long been observed that the microenvironment of FDC plays a crucial role in T-cell-dependent antigen response. The FDC meshwork, formed on antigen challenge attracts all activated B cells and assists them in meeting factors they need for their final maturation. Though FDC are probably not autonomous they seem to play a significant role in integrating germinal center events. In this paper we speculate on how FDC function is coordinated and which kinds of interaction take place between FDC and lymphocytes, in the light of our recent finding of direct intercellular communi- cation through gap junctions in the lymphoid germi- nal center. RESULTS AND DISCUSSION Gap-Junction Expression in Lymphoid Organs Of the three most prevalent gap-junction types, Cx43, -32, and-26, only Cx43 was found in the lymphor- eticular system, that is, in bone marrow (Rosendaal et al., 1991, 1994), thymus (Alves et al., 1995), and secondary lymphoid organs (Krenacs and Rosendaal, 1995). The remarkable feature of gap-junction expression in spleen, lymph nodes, and MALT (the mucosa associated lymphoid tissue) is the presence of large numbers of Cx43 gap junctions in germinal centers of fully formed secondary follicles (Figure 1A). Transmission and freeze-fracture electron micro- scopy and immunohistochemistry revealed that most junctions are produced by FDC, which also express CD21, CD35 complement receptors, and form desmo- somal junctions (Krenacs and Rosendaal, 1995; Krenacs et al., 1997) (Figure 1B). The number of FDC and gap junctions shows a strong positive correlation, being densest in the light zone (Figure 2), where B-cell selection is held to happen (Lindhout et al., 1993). Here, gap junctions are arranged along the processes of FDC that envelope nondividing cen- trocytes. 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). Two of the interesting questions these findings raise are: (1) Why do FDC need to produce lots of gap junctions when they form germinal centers? (2) Do only FDC utilize gap-junctional communication or is this pathway also part of FDC-B-cell interactions? Cell Coupling in the Germinal Center To find out whether the presence of gap junctions means functional coupling between germinal center cells, we set up FDC-B-cell cultures from human tonsils. Separated FDC soon started forming gap junctions in their membranes as they developed