Marginal zone (MZ) B cells are strategically located at the interface between the circulation and the white pulp of the spleen, where they provide a first line of defence by rapidly producing IgM and class-switched IgG antibodies in response to infections by blood-borne viruses and encapsulated bacteria. Mouse MZ B cells primarily express a non-mutated B cell receptor (BCR) and enter the circulation only to shuttle antigens to the follicle, whereas human MZ B cells express a mutated BCR and extensively recirculate.MZ B cells may also produce IgM and class-switched IgG and IgA antibodies in response to commensal antigens that physiologically translocate from the intestinal mucosa to the general circulation in the absence of infection. This innate-like humoral response may generate a ready-to-use pre-immune antibody repertoire that provides a rapid systemic line of defence not only against pathogens, but also against commensal bacteria that breach the mucosal barrier.In mice, MZ B cells originate from splenic transitional stage 2 B cells via a pathway involving the BCR, the B cell-activating factor (BAFF) receptor and the receptor NOTCH2. In humans, some MZ B cells may arise from immature or transitional B cells located in the liver and mesenteric lymph nodes via a fetal pathway involving NOTCH2, whereas other MZ B cells may emerge from transitional or germinal centre B cells located in the spleen through a postnatal pathway involving the BCR, Toll-like receptors (TLRs) and CD40.MZ B cells have a lower activation threshold than follicular B cells, which permits the rapid initiation of IgM production and of IgG- and IgA-inducing class-switch recombination (CSR) in the absence of CD40-dependent help from T follicular helper (TFH) cells. This T cell-independent pathway requires dual BCR and TLR engagement by conserved microbial antigens together with co-stimulatory signals from dendritic cells, macrophages and neutrophils via various cytokines, including BAFF, a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), IL-10, IL-21, interferon-α (IFNα), IFNβ and CXC-chemokine ligand 10 (CXCL10).MZ B cells can also undergo T cell-dependent antibody production by following either a follicular pathway involving CD40-dependent help from germinal centre TFH cells or an extrafollicular pathway involving CD40-dependent help from extrafollicular TFH cells or invariant natural killer T (iNKT) cells. In addition to expressing CD40 ligand, TFH and iNKT cells secrete various CSR- and antibody-inducing cytokines, including IL-4, IL-21 and IFNγ.In humans, MZ B cells probably have a heterogeneous ontogeny and can undergo somatic hypermutation both before and after birth through either an extrafollicular T cell-independent or a follicular T cell-dependent pathway. The extrafollicular T cell-independent pathway diversifies MZ B cells mainly during fetal life or after postnatal exposure to conserved commensal antigens or native polysaccharides, whereas the follicular T cell-dependent pathway may diversify MZ B cells predominantly after postnatal exposure to proteins or protein-conjugated polysaccharides.
