Long-term retention of antigens in germinal centers is controlled by the spatial organization of the follicular dendritic cell network

Abstract

Germinal centers (GCs) require sustained availability of antigens to promote antibody affinity maturation against pathogens and vaccines. A key source of antigens for GC B cells are immune complexes (ICs) displayed on follicular dendritic cells (FDCs). Here we show that FDC spatial organization regulates antigen dynamics in the GC. We identify the existence of a broader FDC heterogeneity within the network. While the entire light zone (LZ) FDC network captures ICs initially, only the central cells of the network function as the antigen reservoir, where different antigens arriving from subsequent immunizations co-localize. Mechanistically, central LZ FDCs constitutively express subtly higher CR2 membrane densities than peripheral LZ FDCs, which strongly increases the IC retention half-life. Even though repeated immunizations gradually saturate central FDCs, B cell responses remain efficient because new antigens partially displace old ones. These results reveal the principles shaping antigen display on FDCs during the GC reaction.

T-cell help in the germinal center: homing in on the role of IL-21

“…IL-4 production is preserved in late-stage GC ( 46 , 47 ). Antigen is abundantly available at the start of the GC response and is preserved late into the GC response by central light zone follicular dendritic cells ( 48 ). CD40 signaling is essential for GC maintenance throughout the GC response ( 49 ).…”

450 million years in the making: mapping the evolutionary foundations of germinal centers

“…These B cells can divide at a much faster rate at an endothermic core body temperature, and so the selective environment becomes increasingly segregated from the wider pool of non-specific clones. Further, only the FDCs at the center of the LZ act as a long-term reservoir of intact antigen in mice ( 134 ). Thus, it appears that the distinct microanatomical structure of the GC intensifies selection pressures by increasing competition for antigen and T cell help, thereby facilitating faster, more efficient selection of higher affinity antigen-specific B cells in endotherms.…”

Protective fibroblastic niches in secondary lymphoid organs

“…Expression of complement receptor 2 (CR2) by non-hematopoietic cells, most likely FDCs, appears to be particularly important for trapping immune complexes in the GC and maintaining high IgG antibody titers ( Fang et al, 1998 ). Indeed, a recent study by Martínez-Riaño et al (2023) showed that the topology of CR2 expression in the FDC network of mouse LNs controls antigen retention. Recording of the long-term dynamics of antigen retention in LNs of mice immunized with fluorescent immune complexes and their replacement upon reimmunization revealed that the entire FDC network contributes to initial antigen capture.…”

“…Recording of the long-term dynamics of antigen retention in LNs of mice immunized with fluorescent immune complexes and their replacement upon reimmunization revealed that the entire FDC network contributes to initial antigen capture. However, only the central FDCs in the LZ retained antigen and served as long-term antigen reservoirs ( Martínez-Riaño et al, 2023 ). It appears that high concentration or repeated antigen exposure leads to dynamic competition of immune complexes for CR2 ( Martínez-Riaño et al, 2023 ).…”

“…However, only the central FDCs in the LZ retained antigen and served as long-term antigen reservoirs ( Martínez-Riaño et al, 2023 ). It appears that high concentration or repeated antigen exposure leads to dynamic competition of immune complexes for CR2 ( Martínez-Riaño et al, 2023 ). Indeed, the view on dynamic FDC antigen retention and replacement is compatible with the progressive replacement of naive B cell clones into long-lived GCs during influenza virus or SARS-CoV-2 infection in mice ( de Carvalho et al, 2023 ).…”