The missing link in the affinity maturation chain

Abstract

Knowledge of the B cell's capacity to recognize native antigen has diluted recognition of the importance of B cell interaction and/or communication with accessory cells to initiate the humoral immune response. In addition, the mechanisms by which antigens gain access to the follicle, and thus to the B cell repertoire, were largely unknown until recently. In the July issue of Nature Immunology, Phan et al.1 extensively characterize the macrophage population located at the follicle junction with the lymph node subcapsular sinus (SCS). The authors show an important role for immune complex relay by SCS macrophages and non-cognate B cells in driving antibody affinity maturation at the germinal centre (GC). Three previous reports highlighted SCS macrophage function in particulate antigen delivery to the primary follicle and its presentation to cognate B cells.2, 3, 4 This unique macrophage population can be now identified phenotypically as CD169hiCD11cloCD11b+F4/80– cells.1 They also express low levels of proteins implicated in the lysosomal machinery (LAMP-1 and LAMP-2; lysosomal proteases), which could explain their ability to retain intact antigen and immune complexes at their surface. Phan et al. show these macrophages are poorly endocytic and have low degradative capacity; they translocate immune complexes unidirectionally across their surfaces, from the SCS to the follicle. Once there, follicular B cells deliver the immune complexes to the membrane of follicular dendritic cells (FDC) in a complement-dependent manner (Figure 1). The molecular mechanisms used by the SCS macrophage to capture antigen and transport it to the follicle remain to be decoded. It is likely that there is a panel of diverse receptors to ensure trapping of any antigen that arrives at the SCS; in addition to complement receptors and Fc receptors, the lectin proteins are interesting candidates for this function. To explain the basis of unidirectional antigen movement over the cell surface, Phan et al.1 suggest a polarized SCS macrophage phenotype that would mediate directional membrane transport. Future studies will shed light on both of these aspects of SCS macrophage biology. The authors also report that SCS macrophages require the B cell-derived cytokine lymphotoxin (LT) for development, homoeostasis and function.1 Similar dependence on B cell LT was previously observed for FDC and marginal zone macrophages.5 In this study, B cell-deficient mice had a greatly reduced SCS macrophage population, which could be partially restored by transfer of wild-type but not of LT-deficient B cells.1 Disruption of the LT supply leads to a reduction in immune complex capture and delivery to follicular B cells in the short run; in the long-range, the SCS macrophage population is almost completely lost.1 These results reinforce the idea that, by continuous communication through LT and the LT receptor with the distinct accessory cells at the follicle, B cells themselves help to maintain the best environment for carrying out their antigen surveillance and response. The GC is an open, dynamic environment in which not only GC B cells, but also follicular B cells enter and move through the FDC network.6, 7, 8 Follicular B cell access was explained as a mechanism that enhances competition and ensures selection of high-affinity B cells. On the basis of the relay of antigen opsonized by newly produced antibodies from SCS macrophages to the FDC surface, Phan et al.1 show a previously undescribed function for follicular B cell shuttling into GC. Non-cognate follicular B cells deliver antigen displayed on SCS macrophages to the surface of FDC in primary follicles.3 Once the primary B cell response is initiated, newly produced specific IgG antibodies opsonize the antigen better than natural antibodies, facilitating antigen capture by SCS macrophages and thus, its delivery to GC by non-cognate follicular B cells.1 As in the case of primary follicles, the B cell-expressed complement receptors, CR1 and CR2, are key players in relaying immune complexes to the GC. The absence of these two receptors on non-cognate follicular B cells leads to a marked reduction in the affinity maturation process, although it does not affect antibody class switching.1 These findings, thus, delineate a mechanism of immune complex delivery to the GC, define its relevance in driving ongoing affinity maturation, and describe the importance of complement receptors, which has been heatedly debated, in the B cell immune response. The presence of immune complex-loaded follicular B cells at the GC raises the question of a role for non-cognate B cells as antigen-presenting cells for cognate B cells, also discussed by Phan et al.1 What would be the outcome of such an interaction? Would it assist or dampen the GC response? An attractive hypothesis is that B cell antigen recognition in the molecular context of the surface of another B cell would have a regulatory function in the GC reaction. This effect would be relevant and/or detectable late in the GC response, in situations that promote a higher frequency of non-cognate B cells carrying immune complexes; for example, when the FDC surface is flooded with newly formed immune complexes, which could impair cargo delivery by non-cognate B cells. The study of Phan et al.1 advances our knowledge on this particular subset of macrophages located at the boundary between the follicle and the SCS. With the help of non-cognate follicular B cells, they provide the source of immune complexes to the GC. SCS macrophages are thus the missing link in the affinity maturation chain. Further studies might be focussed to dissect the molecular mechanisms that SCS macrophages use to accomplish their functions, a knowledge of high biomedical interest for vaccine design. Immune complex relay to the germinal centre. Opsonized antigen, by newly generated specific antibodies, is captured by macrophages at the subcapsular sinus (SCS) of the lymph node. These immune complexes (IC) then translocate across the surface of the macrophage to the follicle by unknown mechanisms. Non-cognate B cells deliver IC from the SCS macrophages to the follicular dendritic cell (FDC) surface at the germinal centre in a complement receptor-dependent manner. During this transit, the migratory B cell bears the cargo at the uropod. This relay of IC to the germinal centre drives the affinity maturation process.