Elsevier

Human Immunology

Volume 76, Issue 9, September 2015, Pages 615-621
Human Immunology

Review
Regulatory B cell: New member of immunosuppressive cell club

https://doi.org/10.1016/j.humimm.2015.09.006Get rights and content

Abstract

Historically, the pivotal role of B cells or B lymphocytes in immunity has been attributed to the production of antibodies. They were also demonstrated to present antigens to T cells and to secrete cytokines, thereby acting as positive regulators in immune responses. A series of studies on autoimmune diseases, however, led researchers to find a unique subset of B cells, later described as “regulatory B cells” (Bregs), that has the ability to suppress immune responses. Bregs occur not only in autoimmune diseases, but also in inflammation and transplantation. Furthermore, recently published literatures suggested that Bregs contributed to the growth and metastasis of certain cancers. In this review, we will discuss these unique subsets of B cells in different kinds of disorders, with particular emphasis on the mechanisms of their immunoregulatory role that were collected from mice and humans.

Introduction

The first clues indicating B cells as immune suppressor by producing “inhibitory antibodies” were found decades ago [1], but significant researches on these negative regulators did not occur until 1996, when Wolf and colleagues proposed that B cells might contribute to the immune deviation from Th1 to Th2 cytokines in murine acute experimental autoimmune encephalomyelitis (EAE) model [2]. Mizoguchi et al. suggested that murine B cells played a suppressive role in the development of colitis by secreting auto-antibodies to clear apoptotic cells in the colon (epithelial cells and lamina propria cells), preventing tissue damage caused by the harmful exposure to self antigens [3]. Mature B cells in mice also functioned by directly eliminating pathogenic CD4+TCRαβ+ T cells or suppressing their proliferation through co-stimulatory molecule interactions such as CD40–CD154 and CD86–CD28, thus inhibited the development of colitis [4]. In the ensuing years after these initial studies, a considerable evidence gathered from various diseases, including autoimmune disorders [5], [6], inflammation [7], [8] and transplantation [9], [10], had reinforced the theory of B cells as potential negatively regulatory cells in immune response.

Though seemly different, cancers and autoimmune diseases are both outcomes of dysfunction of immune regulatory machinery that should be in precise control of protecting oneself and attacking the enemies-lack of immune regulation facilitates autoimmune diseases, while over-suppression of immune effectors results in cancer development [11]. The extensive set of evidence confirmed the negative role of B cells in immune-related diseases in both mice and humans. Whether suppressive B cells are hijacked by cancer cells to defeat anti-tumor immune responses remains to be established. There were clinical observations that B cell infiltration was correlated with poor outcome in metastatic ovarian carcinoma [12]. B-cell knockout mice also showed enhanced anti-tumor immunity after challenge with certain tumors [13], suggesting that B cells can function as negatively regulatory cells in some tumor settings. What’s more, recent data from BALB/c murine model first showed the existence of a unique subset of B cells that can promote breast cancer lung metastasis [14]. In this review, we will highlight the phenotypes, origin, possible roles and mechanisms of regulatory B cells (Bregs) in autoimmune diseases, inflammation, transplantation and cancers in mice and humans.

Section snippets

Various phenotypes of Bregs

Until recently, the exact surface molecules of Bregs have been elusive. Various markers, alone or combined with others, were used to identify Bregs in immune-related diseases. Previous studies in mice identified Bregs as CD5+ B1a cells, CD21+CD23 marginal zone (MZ) cells or CD1d+CD21+CD23+IgMhi transitional 2 marginal zone precursor (T2-MZP) B cells [15]. Later an IL-10-producing Breg subpopulation with a phenotype of CD1dhiCD5+CD19+, termed as B10 cells, was demonstrated to be suppressive in

Origin of Bregs

Mauri et al. proposed that Bregs arised from a common progenitor, named T2-MZP B cells, as they encompass most of the indicated markers for Bregs [36]. T2-MZP B cells are at immature developmental stage and highly responsive to BCR engagement [37], [38]. In the presence of toll like receptor (TLR) ligands, they released first wave of IL-10 [36], [39]. As inflammation cascade ensued, B cells received BCR, CD40, or CD80/CD86 activating signals, and robustly enhanced IL-10 production [16], [36],

Function and mechanisms of Breg in immune-related diseases

Since the discovery of suppressive B cells, scientists have begun to unravel how Bregs suppress immune responses. Different laboratories have confirmed that the production of IL-10 represented the main mechanism of heterogeneous Bregs’ actions.

Bregs in cancers

The role of B cells in cancer biology is complicated and somewhat controversial. Previous evidences confirmed the existence of tumor-infiltrating B cells in solid tumors, but contradicted to each other on their indications. Some researchers found more infiltration of B cells were correlated with better prognosis in ovarian cancers [67], while others concluded the opposite [12]. In murine models, B cell- and T cell-deficient C57BL/6 Rag2−/− mice were resistant to

Target therapy based on Bregs

In autoimmune disease and inflammation models, it has been shown that the elimination of B cells accelerated the disease while the transfer of B cells rescued from the disease progression [76], [77]. Tim-1, an exclusive marker for IL-10+ Bregs, could serve as a therapy target. In a murine model, Tim-1–agonistic antibody significantly enhanced allograft survival by increasing the number of Tim-1+ B cells as well as augmenting their ability to express IL-10 [31]. Early adoptive transfer of B10

Conclusion

The immunoregulatory activity of Bregs has been demonstrated in various studies of inflammation, autoimmunity, and transplantation. Topics such as the markers used to define Bregs, the signaling pathways involved in the activation of Bregs, and the differentiation status of these cells need to be researched further. Though diverse subsets of Bregs utilize various ways to exert regulatory effects, including secreting suppressive cytokines, anto-antibodies and direct cell–cell contact via

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

The authors thank John E. Anderson, M.D. from Johns Hopkins University for providing his assistant for checking grammar mistakes throughout the text. This work was financially supported by research foundation of Tianjin Medical University Cancer Institute and Hospital (Grant B1309).

References (84)

  • W. van de Veen et al.

    IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses

    J. Allergy Clin. Immunol.

    (2013)
  • J.B. Petro et al.

    Transitional type 1 and 2 b lymphocyte subsets are differentially responsive to antigen receptor signaling

    J. Biol. Chem.

    (2002)
  • J. Booth et al.

    Novel B regs down-regulate TLR9-induced cytokine responses in sheep Peyer’s patches

    Vet. Immunol. Immunopathol.

    (2012)
  • J. Berthelot et al.

    Regulatory B cells play a key role in immune system balance

    Joint Bone Spine

    (2013)
  • M. Matsumoto et al.

    The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production

    Immunity

    (2011)
  • P. Natarajan et al.

    Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF-beta, and co-localize with CD4+Foxp3+ T cells

    Mucosal Immunol.

    (2012)
  • T. Tretter et al.

    Induction of CD4+ T-cell anergy and apoptosis by activated human B cells

    Blood

    (2008)
  • S. Lemoine et al.

    Human T cells induce their own regulation through activation of B cells

    J. Autoimmun.

    (2011)
  • A. Morva et al.

    Maturation and function of human dendritic cells are regulated by B lymphocytes

    Blood

    (2012)
  • Y. Shao et al.

    Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway

    Cancer Lett.

    (2014)
  • D. Le Huu et al.

    Donor-derived regulatory B cells are important for suppression of murine sclerodermatous chronic graft-versus-host disease

    Blood

    (2013)
  • A. Morris et al.

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

    J Immunol.

    (1968)
  • S.D. Wolf et al.

    Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice

    J. Exp. Med.

    (1996)
  • A. Mizoguchi et al.

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

    J. Exp. Med.

    (1997)
  • E. Mizoguchi et al.

    Regulatory role of mature B cells in a murine model of inflammatory bowel disease

    Int. Immunol.

    (2000)
  • T. Cantaert et al.

    Increased numbers of CD5+ B lymphocytes with a regulatory phenotype in spondylarthritis

    Arthritis Rheum.

    (2012)
  • P. Scapini et al.

    B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

    Proc. Natl. Acad. Sci. U.S.A.

    (2011)
  • Y. Liu et al.

    Role of IL-10-producing regulatory B cells in control of cerebral malaria in Plasmodium berghei infected mice

    Eur. J. Immunol.

    (2013)
  • H.M. Silva et al.

    Preserving the B-cell compartment favors operational tolerance in human renal transplantation

    Mol. Med.

    (2012)
  • A. Biragyn et al.

    Generation and identification of tumor-evoked regulatory B cells

    Methods Mol. Biol.

    (2014)
  • H.P. Dong et al.

    NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma

    Am. J. Clin. Pathol.

    (2006)
  • S. Inoue et al.

    Inhibitory effects of B cells on antitumor immunity

    Cancer Res.

    (2006)
  • P.B. Olkhanud et al.

    Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4(+) T cells to T-regulatory cells

    Cancer Res.

    (2011)
  • I. Kalampokis et al.

    IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

    Arthritis Res. Ther.

    (2013)
  • A. Das et al.

    IL-10-Producing regulatory b cells in the pathogenesis of chronic hepatitis B virus infection

    J Immunol

    (2012)
  • F. Flores-Borja et al.

    CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation

    Sci. Transl. Med.

    (2013)
  • L.E. van der Vlugt et al.

    CD24(hi)CD27(+) B cells from patients with allergic asthma have impaired regulatory activity in response to lipopolysaccharide

    Clin. Exp. Allergy

    (2014)
  • B. Zha et al.

    Decrease in proportion of CD19+ CD24(hi) CD27+ B cells and impairment of their suppressive function in Graves’ disease

    PLoS ONE

    (2012)
  • J. Noh et al.

    Presence of foxp3-expressing CD19(+)CD5(+) b cells in human peripheral blood mononuclear cells: Human CD19(+)CD5(+)Foxp3(+) regulatory b cell (Breg)

    Immun. Netw.

    (2010)
  • T. Matsushita et al.

    Identifying regulatory B cells (B10 cells) that produce IL-10 in mice

    Methods Mol. Biol.

    (2011)
  • Q. Ding et al.

    Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice

    J. Clin. Invest.

    (2011)
  • S. Xiao et al.

    Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice

    Proc. Natl. Acad. Sci.

    (2012)
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