The ‘short’ history of regulatory B cells

doi:10.1016/j.it.2007.10.004

Trends in Immunology

Volume 29, Issue 1, January 2008, Pages 34-40

https://doi.org/10.1016/j.it.2007.10.004 Get rights and content

The maintenance of tolerance is the sine qua non of a sophisticated regulatory apparatus to prevent or dampen overzealous immune responses. In addition to the ability of B cells to prime and activate the immune system, B cells with regulatory function (Bregs) have been identified in experimental models of autoimmunity, infections, and cancer, supporting the notion that, similar to regulatory T cells (Tregs), Breg-mediated suppression is an important means for the maintenance of peripheral tolerance. This regulatory function appears to be directly mediated by the production of IL-10 and/or TGFβ and by the ability of B cells to interact with pathogenic T cells to inhibit harmful immune responses. The identification of their existence is of great relevance to the understanding of autoimmune diseases and to the development of new therapeutic strategies.

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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Trends in Immunology

ReviewThe ‘short’ history of regulatory B cells

Section snippets

First clues to their existence

Bregs and autoimmunity

Bregs in parasitic infection

Bregs in cancer

Regulatory B cells in transplantation

Environmental factors in the generation of Bregs

Identification of the transitional 2-T2-MZP B cell as Bregs

Is there a link between regulatory lymphocytes?

Can we identify Bregs in humans?

Outstanding questions and conclusions

Acknowledgements

Cell. Immunol.

Cell. Immunol.

Immunity

Lancet

Cell. Immunol.

Blood

J. Invest. Dermatol.

Blood

Immunol. Today

Regulation of cellular antibody synthesis effect of adoptively transferred antibody-producing spleen cells on cellular antibody synthesis

J. Immunol.

Stimulation of regulatory T cell circuits by immunoglobulin-dependent structures on activated B cells

Eur. J. Immunol.

A regulatory role for the memory B cell as suppressor-inducer of feedback control

J. Exp. Med.

Recognition and response to alloantigens in vivo. II. Priming with accessory cell-depleted donor allogeneic splenocytes: induction of specific unresponsiveness to foreign major histocompatibility complex determinants

J. Immunol.

Resting B lymphocytes as APC for naive T lymphocytes: dependence on CD40 ligand/CD40

J. Immunol.

Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice

J. Exp. Med.

B cells present antigen to CD4+ T cells, but fail to produce IL-12. Selective APC for Th2 cell development?

Ann. N. Y. Acad. Sci.

B cells regulate autoimmunity by provision of IL-10

Nat. Immunol.

Suppressive role of B cells in chronic colitis of T cell receptor α mutant mice

J. Exp. Med.

Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-β1 secretion and the resolution of inflammation

J. Clin. Invest.

Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice

J. Immunol.

B cell developmental requirement for the G α i2 gene

J. Immunol.

Cells of the synovium in rheumatoid arthritis. B cells

Arthritis Res. Ther.

Prevention of arthritis by interleukin 10-producing B cells

J. Exp. Med.

Inhibitory effects of B cells on antitumor immunity

Cancer Res.

Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process

Nat. Med.

Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40

Science

Normal Th1 development following long-term therapeutic blockade of CD154-CD40 in experimental autoimmune encephalomyelitis

J. Clin. Invest.

Preclinical evaluation of tolerance induction protocols and islet transplantation in non-human primates

Immunol. Rev.

Recombinant CD40 ligand stimulation of murine B cell growth and differentiation: cooperative effects of cytokines

Eur. J. Immunol.

Human B cell precursors proliferate and express CD23 after CD40 ligation

J. Exp. Med.

Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen

J. Exp. Med.

Bidirectional regulation of human B cell responses by CD40-CD40 ligand interactions

J. Immunol.

Review
The ‘short’ history of regulatory B cells