Trends in Immunology
ReviewThe ‘short’ history of regulatory B cells
Section snippets
First clues to their existence
The hypothesis that suppressor or regulatory B (Bregs) cells orchestrate the immune system was originally proposed in the 1970s and maintains that the suppressive function of B cells was mainly restricted to their ability to produce ‘inhibitory’ antibodies [1]. These initial findings were later followed by a flurry of seminal papers supporting a ‘suppressive framework’ for B cells and introducing a link with T-cell tolerance; in vivo studies showed that adoptive transfer of antigen-activated B
Bregs and autoimmunity
Despite the availability of the above-described data in the literature, the potential role of B cells in the immunoregulation of infections and autoimmunity was mostly overlooked for at least another decade. Janeway and his collaborators were the first to demonstrate an immunoregulatory role for B cells in autoimmune disease by showing that B-cell-deficient mice (μMT), immunized with Myelin Basic Protein (MBP) peptide in Complete Freund's Adjuvant (CFA), failed to control experimental
Bregs in parasitic infection
Although the number of studies describing Bregs during infections is increasing, conclusive interpretation of the current data has been hampered by conflicting results. The first clue for an anti-inflammatory role of Bregs in infections with parasites came from a study showing that μMT mice infected with the helminth Schistosoma mansoni mounted a stronger Th1 response against the helminth egg antigen compared with wild-type mice, in which a Th2-type response predominated. Despite the inhibition
Bregs in cancer
Given that Bregs have been shown to suppress autoimmunity via the inhibition of autoreactive T cells, it might be anticipated that Bregs could also downregulate the protective cytotoxic T lymphocyte responses directed against tumor cells. Indeed, enhanced antitumor immunity can be seen in B-cell-deficient mice and is associated with an increased activity of T and NK cells, both of which are important for the promotion of natural tumor surveillance [36].
Scott and colleagues have now shown that
Regulatory B cells in transplantation
B-cell regulatory action has also been shown in the context of graft versus host disease (GVHD) directed against MHC antigens. Host B cells attenuate CD4+ T-cell proliferation, suppress Th1 differentiation, and inhibit the GVHD response [40] after MHC disparate bone marrow transfer. The absolute requirement for host APC in the induction of GVHD has been previously demonstrated [41]. It is now clear that whereas host DCs are required for the induction of GVHD, host B cells counterbalance the
Environmental factors in the generation of Bregs
UV sensitization is known to inhibit the immune response to different bacterial, fungal, and viral antigens 42, 43, 44. Ullrich and collaborators have recently established that IL-10-producing lymph node B cells, at least in part, mediated this UV-induced tolerance. Interestingly, induction of tolerance by B cells is mediated by the release and binding of platelet activating factor (PAF) and serotonin. This tolerizing effect might be indirect because B cells express both the PAF receptor and
Identification of the transitional 2-T2-MZP B cell as Bregs
B cells, and in particular B1 cells in the peritoneal cavity, have long been known to be a rich source of IL-10 [46], and, recently, their actions have been shown to be responsible for the susceptibility of infants to infectious disease [47]. Amongst conventional B cells of the B2 lineage, Marginal Zone (MZ) B cells have been found to produce elevated levels of IL-10 upon LPS, or upon CpG stimulation 15, 48. Additional in vivo results have shown that MZ B cells participate in the suppression of
Is there a link between regulatory lymphocytes?
The recent findings of a link between Bregs and Tregs, CD4+CD8+ T cells, and NK T cells 56, 57, 58 have uncovered an additional strategy embraced by the immune system to efficiently react to environmental challenges and prevent autoimmunity: the ability of Bregs cells to regulate and/or generate Tregs. The relevance of Breg to Treg activity was initially proposed in the ACAID model. In this system, the generation of Tregs is dependent upon presentation of the eye's anterior chamber (AC)
Can we identify Bregs in humans?
In comparison to the wealth of data relating to Tregs, little is known regarding the possible existence of Bregs in humans. It is clear that activated human B cells, similar to the mouse B cells, can produce significant quantities of cytokines that might influence the pathological environment 60, 61. Depending on the signals B cells receive, pro- or anti-inflammatory cytokines can be produced. One group, in parallel with the murine studies described above, demonstrated that, whereas CD40
Outstanding questions and conclusions
In mice, there are clearly various subsets of Bregs that possess immunoregulatory properties (Table 1). In the coming years, these will need to be better defined, and their phenotype will need to be more closely correlated with their function in vivo.
Topics such as antigen specificity, the location at which Bregs exert their function, the means by which Bregs function in autoimmunity as well as in other immune-related disorders, and the methods we can use to expand them in vivo for therapy need
Acknowledgements
We thank P.A. Blair for helpful discussions.
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