The Shaping of a B Cell Pool Maximally Responsive to Infections

Abstract

B cell subsets differ in development, tissue distribution, and mechanisms of activation. In response to infections, however, all can differentiate into extrafollicular plasmablasts that rapidly provide highly protective antibodies, indicating that these plasmablasts are the main humoral immune response effectors. Yet, the effectiveness of this response type depends on the presence of antigen-specific precursors in the circulating mature B cell pool, a pool that is generated initially through the stochastic processes of B cell receptor assembly. Importantly, germinal centers then mold the repertoire of this B cell pool to be increasingly responsive to pathogens by generating a broad array of antimicrobial memory B cells that act as highly effective precursors of extrafollicular plasmablasts. Such B cell repertoire molding occurs in two ways: continuously via the chronic germinal centers of mucosal lymphoid tissues, driven by the presence of the microbiome, and via de novo generated germinal centers following acute infections. For effectively evaluating humoral immunity as a correlate of immune protection, it might be critical to measure memory B cell pools in addition to antibody titers.

Keywords: B cell repertoire; B cell subsets; antibodies; extrafollicular foci; extrafollicular responses; germinal centers; host-pathogen interaction; immunity.

Figure 1. B cell responses to infections

Activation of antigen-specific B cells results in their accumulation in the T-B border zone of lymphoid tissue where they receive costimulatory signals through interaction with CD4 T cells or iNKT cells via classical and non-classical MHC interactions, respectively. Co-stimulation may also occur in a non-cognate manner through secretion of cytokines. Based on the quality of these signals, B cells will remain outside the follicle or reenter the follicles to start germinal center responses. B cells can regain quiescence as switched or non-switched MBC, or they rapidly differentiate into antibody-secreting plasmablasts forming “extrafollicular foci” (EF), major sources of antibodies early in infection. GC facilitate the shaping of the responding B cell clones through clonal expansion and introduction of high numbers of mutations in the antigen-binding sites of the BCR and subsequent selection of effective antigen-binders that interact productively with T cells. In contrast to extra-follicular MBC, GC-derived MBC provide a diversified source of responders that can feed into the EF response. Alternatively, B cells leave already programed for terminal differentiation into antibody-secreting plasma cells.

Figure 2. Rapidly generated extrafollicular-derived antibodies provide immune protection and regulate pathogen-specific B cell responses

Extrafollicular foci rapidly form after infection and secrete both IgM and class-switched antibodies. Both IgG and IgM provide rapid protection by opsonization of the pathogen for uptake by macrophages and neutrophils via binding of antibody-antigen complexes to activating FcgR or when tagged with complement to complement receptors CR1/2 (CD35/21). They may also directly bind to and neutralize pathogens. Support for B cell activation is provided through provision of costimulatory signals via binding to CD21, the deposition of antigen onto the B cell surface, which may facilitate binding to the BCR, or via transport of immune complexes on the surface of FOB cells to FDCs situated inside the follicles, thereby supporting germinal center responses. Secreted IgM and the B cell-expressed FcμR also provide B cell activation, albeit the mechanisms underlying their effects are currently unknown.

Figure 3. Shaping of the mature B cell pool by chronic and acute germinal centers generates a pool of B cells with increased responsiveness to microbial challenges

Transitional B cells continuously emerge from the bone marrow with a largely stochastically-derived BCR repertoire. During transition into the mature B cell pool in the spleen, the repertoire is altered through removal of strongly autoreactive B cells. The chronic germinal centers in the Peyer’s patches as well as mucosal lymph nodes further shape the B cell pool by expanding and selecting B cells that recognize microbial antigens. Rapid extrafollicular plasmablasts are selected from this diverse pool of B cells either through activation of naïve, switched or non-switched MBC. The latter are major precursor pools with a predilection for differentiation into EF responses. Further repertoire shaping occurs following infections in de novo developing germinal centers and that contribute not only MBC but also into plasma cells that will reside long-term in the bone marrow.