Marginal Zone B-Cells, a Gatekeeper of Innate Immunity

Abstract

To maintain the integrity of an organism constantly challenged by pathogens, the immune system is endowed with a variety of cell types. B lymphocytes were initially thought to only play a role in the adaptive branch of immunity. However, a number of converging observations revealed that two B-cell subsets, marginal zone (MZ) and B1 cells, exhibit unique developmental and functional characteristics, and can contribute to innate immune responses. In addition to their capacity to mount a local antibody response against type-2 T-cell-independent (TI-2) antigens, MZ B-cells can participate to T-cell-dependent (TD) immune responses through the capture and import of blood-borne antigens to follicular areas of the spleen. Here, we discuss the multiple roles of MZ B-cells in humans, non-human primates, and rodents. We also summarize studies – performed in transgenic mice expressing fully human antibodies on their B-cells and in macaques whose infection with Simian immunodeficiency virus (SIV) represents a suitable model for HIV-1 infection in humans – showing that infectious agents have developed strategies to subvert MZ B-cell functions. In these two experimental models, we observed that two microbial superantigens for B-cells (protein A from Staphylococcus aureus and protein L from Peptostreptococcus magnus) as well as inactivated AT-2 virions of HIV-1 and infectious SIV preferentially deplete innate-like B-cells – MZ B-cells and/or B1 B-cells – with different consequences on TI and TD antibody responses. These data revealed that viruses and bacteria have developed strategies to deplete innate-like B-cells during the acute phase of infection and to impair the antibody response. Unraveling the intimate mechanisms responsible for targeting MZ B-cells in humans will be important for understanding disease pathogenesis and for designing novel vaccine strategies.

Loss of marginal zone B-cells in SHIVSF162P4 challenged rhesus macaques despite control of viremia to low or undetectable levels in chronic infection

“…Our LN data during early chronic phase, wk8 post-infection, showed a similar decrease, which persisted in splenic MZ B cells in late chronic phase. This overall decline might be attributable to differentiation of these cells into antibody secreting cells which lose the CD21 hi phenotype as described by Zouali and Richard (Zouali and Richard, 2011). We confirmed in preliminary experiments using ex-vivo TLR ligand stimulation of rhesus macaque splenic B cells that CD21 hi cells are lost 3 days post-stimulation (unpublished).…”

“…Colombo et al (2013) reported human splenic MZ B-cells to be CD38 − while Benitez et al (2014) by gating on CD24 and CD38 identified a B-cell population in human spleen characteristic of MZ B-cells that was CD38 + CD21 hi . MZ B-cells play a role in the early immune response to pathogens in a T-independent and T-dependent fashion (Zouali and Richard, 2011). CD38 has been shown to be important for the innate response to Listeria infection (Lischke et al, 2013).…”

Lack of B Cell Dysfunction Is Associated with Functional, gp120-Dominant Antibody Responses in Breast Milk of Simian Immunodeficiency Virus-Infected African Green Monkeys

“…Still, the rise in the proportion of activated memory and marginal-zone B cells in all RhMs, but not AGMs, during chronic SIV infection could contribute to the elevated systemic IgG levels observed during pathogenic infection. Activated memory B cells are induced in response to ongoing viral replication and eventually undergo differentiation into Ig-secreting plasmablasts (45), and marginal-zone B cells play a role in priming T cell-dependent IgG production in response to infection (64). Therefore, it is conceivable that these B cell subsets are partially responsible for the hypergammaglobulinemia observed during chronic SIV infection in RhMs.…”

B Cells Modulate Systemic Responses to Pneumocystis murina Lung Infection and Protect On-Demand Hematopoiesis via T Cell-Independent Innate Mechanisms when Type I Interferon Signaling Is Absent

“…In contrast, marginal zone B cells act as gatekeepers of innate immunity that modulate maturation and function of innate immune cells, including dendritic cells (DCs), resulting in profound immune suppression. Communication between these "innate-like" B cells and DCs is at least in part facilitated via secretion of IL-10 and CD40-CD40 ligand (CD40L) interaction (73,74). Although both follicular and marginal zone B cells are capable of producing substantial amounts of IL-10, innate-like B cells are able to produce IL-10 independent of B-cell receptor-mediated stimulation but as the result of innate immune activation (75).…”