Fig. 10.15 Selection for high-affinity mutants in the germinal center relies on help provided by TFH cells. After activated B cells interact with TFH cells at the follicle border, they migrate to germinal centers (GCs), where the following events depicted here occur. In the dark zone of the GC, somatic hypermutation alters the immunoglobulin V regions (first panel). In some B cells (yellow), the mutated B-cell receptor (BCR) will have low or no affinity for the antigen, while in other B cells (orange) the mutated BCR affinity may be higher. After exiting the dark zone, the B cells with higher-affinity BCRs will capture antigen (red) trapped on follicular dendritic cells (FDCs) and then process and present it on MHC class II molecules (second panel). B cells with low-affinity BCRs will fail to capture and present antigen. B cells that present linked antigen epitopes to TFH cells will receive help through CD40L and IL-21, which promote survival and proliferation. B cells that lack antigen on MHC class II molecules receive no help and will eventually die (third panel). Some of the proliferating B cells undergo repeated cycles of entry to the dark zone, mutation, and selection (fourth panel), and other progeny B cells undergo differentiation to either memory B cells or plasma cells (not shown).
Fig. 10.16 Antigens are trapped in immune complexes that bind to the surface of follicular dendritic cells.
Radiolabeled antigen localizes to, and persists in, lymphoid follicles of draining lymph nodes (see the light micrograph and the schematic representation (middle panel), showing a germinal center in a lymph node). The intense dark staining shows the localization in the germinal center of radiolabeled antigen that had been injected 3 days previously. The antigen is in the form of antigen:antibody:complement complexes bound to Fc receptors and to complement receptors CR1 or CR2 on the surface of the follicular dendritic cell (FDC), as depicted in the right-hand panel and inset. These complexes are not internalized, as such antigen can persist in this form for long periods. Photograph courtesy of J. Tew.
10-8 Positive selection of germinal center B cells involves contact with TFH cells and CD40 signaling.
Selection of B cells with improved affinity for antigen occurs in increments. It was originally discovered in vitro that resting B cells could be kept alive by simultaneously cross-linking their B-cell receptors and ligating their cell-surface CD40. In vivo these signals are delivered by antigen and by TFH cells, respectively. The details of selection in the germinal center have become more clear recently from in vivo two-photon microscopic studies (see Appendix I, A-10) that show that positive selection of a B cell depends on the B cell’s ability to take up antigen, and to receive signals delivered by TFH cells. It is thought that somatic hypermutation occurs in the centroblasts in the dark zone; when a centroblast reduces its rate of proliferation and becomes a centrocyte, it increases the number of B-cell receptors on its surface and moves to the light zone, where there are abundant FDCs. Antigen can be trapped and stored for long periods in the form of immune complexes on FDCs (Fig. 10.16 and Fig. 10.17). The centrocyte’s ability to bind antigen determines its relative ability to acquire