ReviewRegulatory B cell: New member of immunosuppressive cell club
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+TCRα−β+ 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).
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