GERMINAL-CENTERS

Germinal centers develop in the B cell follicles of secondary lymphoid tissues during T cell-dependent (TD) antibody responses. The B cells that give rise to germinal centers initially have to be activated outside follicles, in the T cell-rich zones in association with interdigitating cells and T cell help. After immunization with a single dose of protein-based antigen, the germinal centers formed are oligoclonal; on average three B blasts colonize each follicle. These blasts undergo massive clonal expansion and activate a site-directed hypermutation mechanism that acts on their immunoglobulin-variable (Ig-v)-region genes. Mature germinal centers are divided into dark and light zones. The proliferating blasts, centroblasts, occupy the dark zone and give rise to centrocytes that are not in cell cycle and fill the light zone. The light zone contains a rich network of follicular dendritic cells (FDC) that have the capacity to take up antigen and hold this on their surface for periods of more than a year. The antigen is held as an immune complex in a native unprocessed form, but the antigen may be taken up from FDC by B cells, which can process this and present it to T cells. Centrocytes appear to be selected by their ability to interact with antigen held on FDC. There is a high death rate among centrocytes in vivo, and when these cells are isolated in vitro, they undergo apoptosis within hours on culture. The onset of apoptosis can be delayed by crosslinking centrocytes' surface Ig, and long-term survival is achieved by signalling through their surface CD40. After activation through CD40 the centrocytes increase their surface Ig and acquire characteristics of memory B cells. These observations suggest centrocyte selection involves uptake and processing of antigen held on FDC and its presentation to T cells that can be induced to express CD40 ligand at the point of cognate interaction. Other signals that induce a proportion of germinal center cells to become plasma cells have also been described. Germinal centers persist for about 3 weeks following immunization, but after this, memory B blasts continue to proliferate in follicles throughout the months of T cell-dependent antibody responses. These cells are probably the source of plasma cells and memory cells required to maintain long-term antibody production and memory after the first 3 weeks of T cell-dependent antibody responses.