|Year : 2019 | Volume
| Issue : 2 | Page : 70-78
B cell counterpart of Treg cells: As a new target for autoimmune disease therapy
Myong-Guk Ri1, Chol-Ho Kang2
1 Center of Clinical Immunology, Pyongyang Medical College, Kim Il Sung University, Pyongyang, Democratic People's Republic of Korea
2 Department of Diagnostic Microbiology and Immunology, Red Cross General Hospital, Pyongyang, Democratic People's Republic of Korea
|Date of Submission||26-Sep-2018|
|Date of Acceptance||17-Sep-2019|
|Date of Web Publication||28-Jan-2020|
Dr. Myong-Guk Ri
Center of Clinical Immunology, Pyongyang Medical College, Kim Il Sung University, Pyongyang
Democratic People's Republic of Korea
Source of Support: None, Conflict of Interest: None
B cells have been considered a positive immune regulator by producing antibodies and presenting antigens to T cells. Recently, it has been shown that B cells comprise rare but potent subset capable of inhibiting immune responses via diverse regulatory mechanisms. This subset of B cells, known as regulatory B cells (Bregs), negatively regulates immune responses and contributes to immune tolerance. Among several regulatory B cell subsets, interleukin 10 (IL-10)-producing regulatory B cells are intensively investigated. Studies in experimental animal models, as well as in patients with autoimmune diseases, have identified Breg subsets exhibiting a powerful therapeutic tool for severe immune disorders. Now, human regulatory B cells are becoming an active area of research. Clear criteria to identify these cell subsets and the key molecular mechanisms underlying their physiological features are required for understanding the complete picture of regulatory B cells. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells.
Keywords: Autoimmune disease, interleukin-10, regulatory B cell
|How to cite this article:|
Ri MG, Kang CH. B cell counterpart of Treg cells: As a new target for autoimmune disease therapy. Indian J Allergy Asthma Immunol 2019;33:70-8
|How to cite this URL:|
Ri MG, Kang CH. B cell counterpart of Treg cells: As a new target for autoimmune disease therapy. Indian J Allergy Asthma Immunol [serial online] 2019 [cited 2020 Feb 24];33:70-8. Available from: http://www.ijaai.in/text.asp?2019/33/2/70/276953
| Introduction|| |
The immune cells with suppressive/regulatory function play a pivotal role in maintaining immune tolerance and in the suppression of autoimmune diseases. Experimental models of transplantation provide a strong support for the role of regulatory cells in tolerance. In 1990, Hall et al. reported that the transplantation of the cells from rats accepting heart allografts following a short course of cyclosporine to naïve rats conferred donor-specific tolerance. Over the subsequent two decades, tremendous strides have been made in our understanding of the immunobiology of regulatory cells and their roles in autoimmunity, infectious diseases, cancers, and transplantation.,,,,,, Hematopoietic cells possess several cell lineages with regulatory properties that may contribute to tolerance to self-antigens and alloantigens. Many, but not all of these regulatory cells express CD4 and CD25 as surface markers. A main property of regulatory cells is the expression of nuclear transcription factor forkhead box protein 3 (FoxP3), which has been shown to be a master transcription factor of Treg development in both mice and humans.,,,, FoxP3+ Treg are predominantly also CD4+ although CD8+ FoxP3+ cells with suppressive properties have been described. CD4+ FoxP3+ Tregs can be divided into two subpopulations: natural Tregs that develop in the thymus and induced Tregs derived from effector T cells in the periphery by foreign antigens. Recently, like T cells, B cells have a dual role in immunity serving both as immune effector and as regulatory cells (Breg). Unlike Tregs, there are no validated molecular or phenotypic markers to define Bregs. Currently, they are defined functionally based on their production of interleukin 10 (IL-10).
| Interleukin-10-Producing Regulatory B Cells|| |
Main component of humoral immunity-B cells have been considered to be a positive regulator of immune responses because of their ability to terminally differentiate into plasma cells and produce antigen-specific antibodies. Therefore, B cells can serve as antigen-presenting cells, leading to optimal antigen-specific CD4+ T cell expansion, memory formation, and cytokine production. B cells may also positively regulate CD8+ T cell responses in mouse models of autoimmune diseases., In addition, costimulatory molecules, such as CD80, CD86, and OX40L, expressed on B cells are also important for optimal T cell activation., Thus, in addition to production of antibodies, B cells can positively regulate cellular immune responses.
Specific B cell subsets, however, negatively regulate immune responses and have been termed regulatory B cells.,,, Despite their short tenure on the immune state, regulatory B cells have garnered considerable attention as important components of the cellular network that modulates the immune system.
The concept of regulatory B cells first seems to be shown in the literature before the phenotypic identification of distinct B cell subsets. B cell-mediated suppression of immune activation was first identified during delayed-type hypersensitivity responses in guinea pigs in 1974., These studies introduced the concept that “suppressor B cells” could regulate T cell function, but this notion fell from favor. However, Wolf et al. reestablished this concept when they demonstrated in 1996 that the disease course of experimental autoimmune encephalomyelitis (EAE) was prolonged in B cell-deficient mice. Mizoguchi et al. subsequently demonstrated a suppressive role for B cells in chronic colitis in 1997 and were the first to publish the term “regulatory B cells” in 2002 to designate B cells that regulate immune responses by secreting IL-10., These studies were accompanied by numerous provocative papers that demonstrated B cell regulatory effects on diverse autoimmune responses.,,,, As anti-inflammatory cytokine IL-10 inhibits immune responses, IL-10 production is not a unique mechanism by which regulatory B cells suppress immunity. Heterogeneity of B cell antigen receptor (BCR) and cell surface receptors unquestionably contributes to the observed functional diversity among B cell populations. The current issue on regulatory B cells highlights the fact that these cells are much diverse in phenotype. For example, although IL-10 production is commonly associated with “regulatory B cells” and is frequently assumed to be their mechanism of negative regulation, some groups have identified population of B cells with IL-10-independent regulatory functions. As no specific phenotypic markers, signaling molecules, or transcription factors have been identified to delineate among regulatory B cell subsets, the functionally important cytokines or cell surface molecules that drive their regulatory function currently offer the best means to identify specific B cell subsets with different functional properties. Thus, regulatory cells do not appear to represent specific lineages within the B cell population, but may delimit B cells that have acquired distinct functional abilities in response to their environmental cues. Lykken et al. outlined the concept that the capacity of B cells to produce IL-10 should be used as the exclusive marker for the regulatory B cell subset known as B10 cells.
Although populations enriched for B10 cells have been identified, there is no specific transcription factor or cell surface marker unique to all B10 cells. Specific marker for determining of B10 cells is the expression/production of IL-10. In general, spleen B10 cells are IgM hi IgD lo CD19hi MHC II hi CD21int/hi CD23lo CD24hi CD43+/− CD93− and therefore share overlapping phenotypic characteristics with multiple B cell developmental subsets, including immature transitional and marginal zone B cells and peritoneal B1 cells. B10 cells are enriched within the splenic CD1d hi CD5+ subset, where B10 cells and B10+B10pro cells represent 15%–20% and 50% of this phenotypic compartment, respectively; however, B10 and B10+B10pro cells can also be found in the CD1d lo and CD5− populations. Spleen and peritoneal B10 cells have similar phenotypes, although peritoneal B cells do not express high levels of CD1d., Spleen B10 cells are also enriched in the T cell immunoglobulin domain and mucin domain protein 1 (TIM-1)+ B cell population, in spite of the fact that B10 cells are additionally found in the TIM-1− population. Mouse B10 cells predominantly localize in the spleen and peritoneal cavity, but also exist in the peripheral and mesenteric lymph nodes and blood and at very low frequencies in gut-associated lymphoid tissues in wild-type (WT) mice.,, Within the peritoneal cavity, B10 cells are most abundant within the CD5+ CD11b + B1a subset, representing close to 20% of this compartment. B10 cells can also be found at lower frequencies within the CD5− CD11b + B1b and CD5− CD11b − B2 subsets, demonstrating that IL-10 competence is not restricted to a specific phenotypically defined B cell subset. Similarly, B10pro cells comprise up to 40% of B1a cells and can also be found in the B1b and B2 compartments. Despite this high frequency of B10 cells within the B1a compartment, B10 cells are numerically higher in the spleen due to the low overall number of B cells in the peritoneal cavity. Likewise, B10+ B10pro cells represent 1%–4% of B cells in the mesenteric lymph nodes, lamina propria, and Peyer's patches and 3%–8% of B cells in the peripheral blood and lymph nodes.
Blood B10 cells from adult humans express heightened levels of CD19 and IgD and the activation and memory markers CD27, CD48, and CD148. Given their expression of memory markers, B10 cells are likely to have encountered their respective antigens in vivo. Relative to immature or transitional B cells, B10 cells express less IgM and do not express CD10. B10 and conventional B cells express similar levels of CD5, CD20, CD21, CD22, CD23, CD25, CD28, and CD40.
Human B10 cells can represent close to 25% of total B cells within the CD42hi CD27+ blood B cell subpopulation, although they are also found in the CD24lo and CD27− subpopulations. Some studies have reported that most B10 cells can be found in the naïve CD27− subpopulation, whereas others have observed an enrichment of regulatory B cells within the CD24hi CD38hi subpopulation following 72 h culture. Human B10 cells have been identified in the spleen, tonsils, and newborn cord blood, where they represent 0.3%–0.8% of total B cells and decrease in number with age. Thus, B10 cells can be in many phenotypically defined subpopulations, demonstrating that IL-10 competence remains the best marker for identifying this specific subset of regulatory B cells.
B cells that are actively producing IL-10, which are functionally defined as “B10 effector cells,” are difficult to identify in vivo due to their very low numbers. However, B10 cells that have been functionally programmed to express IL-10 in vivo, and are thereby IL-10 competent, are identified by the production of IL-10 ex vivo following stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin, which stimulate protein kinase C and calcium transport, respectively. Acute B cell stimulation with PMA and ionomycin is a useful method for identifying IL-10-competent B10 cells.,
| Signals Controlling for Interleukin-10 Production by B Cells|| |
In terms of the signaling events governing B cell suppressive function, common features that may provide some insight into regulatory B cells have been established. A consensus is developing that Toll-like receptors (TLRs), CD40,, BCR, and combinations of them drive the signaling that confers a suppressive role on B cells. Many studies have established TLR signaling to be essential for IL-10 production., In vitro stimulation with TLRs induces IL-10 production by naïve B cells; however, on stimulation with BCR and CD40, naïve B cells do not secrete IL-10., Although the indispensability of TLR signals for the in vivo suppressive function of B cells has also been confirmed by genetic approaches in EAE, signals via TLRs are not sufficient to adequately inhibit EAE. Given that EAE is not successfully inhibited in mice with a B cell-specific deletion of CD40 or by mice with all B cells expressing the same irrelevant BCR, activation of BCR and CD40 is thought to be required for the in vivo regulatory function of B cells.
CD40 interaction with CD40L induces B cell activation and plasma cell differentiation. CD40 ligation on B cells results in the activation of STAT3, nuclear factor κB, and extracellular signal-regulated kinases, which are suggested regulators of IL-10 induction in T cells, dendritic cells, and macrophages. Although there is no direct evidence in murine B cells, CD40 engagement induced marked activation of STAT3 and enhanced IL-10 secretion by human naïve B cells.,
Evidence for the mechanism by which the BCR signaling pathway contributes to B cell IL-10 production is increasing. On encountering their cognate antigens via BCR, B cells are activated and differentiate into plasma cells. A key response to BCR stimulation is the increase in cytosolic Ca 2+ concentration due to the release of Ca 2+ from the endoplasmic reticulum (ER) and Ca 2+ influx from the extracellular space. BCR stimulation activates the proximal kinases, subsequently activating phospholipase C-γ2 (PLCγ2) through B cell linker protein (BLNK). Activated PLCγ2 yields inositol 1, 4, 5-trisphosphate, which allows the release of Ca 2+ from ER stores, and the resulting decrease in Ca 2+ in the ER lumen in turn triggers the entry of Ca 2+ across membranes via Ca 2+ channels. This process is known as store-operated Ca 2+ entry (SOCE), which is essential for maintaining sustained Ca 2+ signaling., SOCE activation is absolutely dependent on stromal interaction molecule 1 (STIM1) and STIM2, which function as ER-resident Ca 2+ sensors. The decrease in ER luminal Ca 2+ induces the STIM proteins to cluster below the plasma membrane, where they physically interact with Ca 2+ channels, leading to SOCE. For a long time, the physiological significance of SOCE was unknown, until a STIM-dependent SOCE was identified as a key signal for B cell regulatory function through IL-10 production. Mice with B cell-specific deletion of STIM proteins exhibited marked exacerbation of EAE development, and B cells lacking both STIM proteins failed to secrete BCR-mediated IL-10. The importance of BCR signals for B cell IL-10 production is further suggested by a study showing that mice lacking BLNK have impaired IL-10 production and increased contact hypersensitivity inflammation.
How does Ca 2+ signaling control IL-10 production? A wide variety of Ca 2+-dependent signaling molecules and transcription factors have been described as candidate regulators of IL-10 expression; however, in the case of B cells, the activation status of only NFAT1 (NFATc2) was impaired in the absence of STIM proteins. NFAT1 is dephosphorylated by Ca 2+-activated phosphatase calcineurin and translocates into the nucleus, where it becomes transcriptionally active. The calcineurin inhibitor cyclosporine A was found to completely suppress IL-10 secretion and silencing of NFAT1 greatly lowered IL-10 production. These findings are consistent with other findings that show the calcineurin-NFAT pathway to be involved in IL-10 production in other immune cells., The above-mentioned data suggest that the BCR-STIM-SOCE-calcineurin/NFAT signaling cascade may be essential for IL-10 production by B cells. It should be noted, however, that B cell-specific ablation of NFAT2 (NFATc1), an inducible NFAT, was found to result in an increase in IL-10-competent B cells, suggesting that members of the NFAT family may have distinct roles in IL-10 expression.
Although B cells can secrete IL-10 after BCR stimulation in a Ca 2+ influx-dependent way, this occurs only when B cells are prestimulated with CD40 and, particularly, TLR agonists such as lipopolysaccharide (LPS)., Why is BCR stimulation alone not sufficient for B cell IL-10 production? Given that NFAT activation is normally observed after stimulation by BCR alone, additional signals might be required. One possible explanation is that TLR signals may alter the chromatin structure at the il10 locus, thereby allowing key transcription factors to access the promoter/enhancer of il10. Indeed, previous studies have suggested the participation of chromatin remodeling in the initial events, leading to IL-10 transcription in several immune cells. Histone deacetylase 11 (HDAC11) has been shown to associate with the distal region of the il10 gene locus and to repress LPS-mediated IL-10 production in antigen-presenting cells.
Because histone deacetylation mediated by HDAC leads to a silent chromatin, HDAC11 may regulate chromatin status and the transcription factor required for IL-10 mRNA transcription.
The most likely scenario is that CD40 and TLR ligation allows B cells to differentiate into IL-10-competent B cells, in which NFAT1, for example, augments IL-10 expression. Given that such stimulators are well-known inducers of plasma cell differentiation, it is reasonable to expect that differentiated plasmablasts or plasma cells are IL-10 producers. In association with this idea, TLR downstream molecules may also function as transcriptional partners of NFAT for IL-10 expression. Indeed, NFAT proteins interact with several transcription factors, including AP-1, IRF4, GATA3, and c-Maf to produce various cytokines in T cells, which suggests that additional TLR-activated components may be required for IL-10 production in B cells or for regulatory B-lineage cell development.
| Role of Regulatory B Cells in Some Immune Pathologies|| |
Although studies of regulatory B cells in clinic are limited, there have been emerging data proposing the importance and potential future therapeutic application of peripheral blood regulatory B cells in human diseases.
The roles of regulatory B cells in a spontaneous lupus model have been closely investigated in two mouse models: New Zealand Black (NZB) × New Zealand White F1 hybrid (NZB/W) mice and MRL/lpr mice.,,, First clinical study using peripheral blood B cells from systemic lupus erythematosus (SLE) patients showed that the frequencies of CD5+ B cells producing IL-10 were significantly higher in SLE patients than those in normal controls, when they were cultured in the presence or absence of PMA and ionomycin or LPS. Another study showed that IL-10 production was closely associated with CD154 expression on B cells, suggesting the importance of cellular activation for IL-10 production, and that the IL-10-producing CD154+ B cells increased aberrantly when peripheral blood mononuclear cells (PBMC) from SLE patients were stimulated with Staphylococcus aureus Cowan1. Yang et al. showed an increase in CD19+ IL-10+ B cells in the blood of SLE patients when the cells were stimulated with LPS for 24 h with additional PMA and ionomycin. Recently, the concept of regulatory B cell dysfunction in autoimmune diseases has been introduced by demonstrating functional impairment of CD24hi CD38hi regulatory B cells in SLE patients. After CD40 stimulation, CD24hi CD38hi regulatory B cells suppressed interferon-γ (IFN-γ) and tumor necrosis factor-α production from CD4+ T cells in normal controls, whereas they did not have the inhibitory effect in SLE patients. This effect was partially dependent on IL-10. CD24hi CD38hi regulatory B cells isolated from peripheral blood of SLE patients were unresponsive to CD40 stimulation and produced less IL-10 than those from normal controls. Another study showed that in SLE patients, FSC hi fractions of B cells stimulated with IL-2 and SAC for 72 h had less suppressive effect on T cell proliferation compared with those from normal controls. Collectively, although regulatory B cells are increased in the peripheral blood of SLE patients, the function of those cells is impaired.
Previously, B cells are considered harmful in rheumatoid arthritis (RA), because B cell depletion therapy using rituximab has been shown to be effective. However, several reports using collagen-induced arthritis (CIA) have demonstrated a protective function and therapeutic potential of regulatory B cells. When B cells from arthritogenic mice were stimulated with collagen and an anti-CD40 monoclonal antibody, they produced high level of IL-10 and low levels of IFN-γ. Induction of CIA was inhibited and the established disease was improved by the adoptive transfer of these B cells into immunized recipient mice, which is accompanied by inhibition of Th1 cell differentiation. This regulatory effect of B cells depends on IL-10 production, because the adoptive transfer of T2-MZP B cells, which are enriched in regulatory B cells as mentioned above, from IL-10-deficient DBA mice failed to prevent development of arthritis. Other than T2-MZP B cells, ex vivo expanded CD1d hi CD5+ regulatory B cells also have the potential to delay CIA onset and ameliorate disease severity through inhibition of Th17 cell differentiation, when adoptively transferred. In a different study, administrating apoptotic thymocytes to mice before the onset CIA resulted in protection from severe joint inflammation and bone destruction. These studies have suggested that regulatory B cells can regulate the disease course and outcome in mouse RA models. In contrast to SLE, analysis of peripheral blood regulatory B cells in RA patients had not been done fairly until recently. Mauri et al. compared the function and the numbers of peripheral blood regulatory B cells from RA patients with those from normal controls. In this study, they showed that CD24hi CD38hi regulatory B cells from normal controls inhibited CD4+ CD25− T cell differentiation into Th1 and Th17 cells and promoted their conversion into regulatory T cells, partially through IL-10 production. By contrast, CD24hi CD38hi regulatory B cells from RA patients failed to suppress Th17 differentiation and convert naïve T cells into functional regulatory T cells. In addition, both the frequency and absolute number of CD24hi CD38hi regulatory B cells were significantly decreased in peripheral blood from RA patients compared with those from normal controls. The frequency of CD24hi CD38hi regulatory B cells in RA patients negatively correlated with the disease activity. On the basis of the multiple reports describing a negative correlation between regulatory B cell number or frequency and disease severity, regulatory B cells may contribute to suppression of the disease in RA patients, although their function may be attenuated.
EAE is an autoimmune disease of the central nervous system (CNS) induced by immunization with myelin proteins or peptides. It is an established MS model that is characterized by acute CNS inflammation, demyelination, and paralysis. The regulatory role of B cells in EAE was first evident in 1996. A regulatory role for B cells was also demonstrated in another model of EAE using proteolipid protein peptide. Matsushita showed that B cell depletion by anti-CD20 mAb treatment 7 days before myelin oligodendrocyte glycoprotein peptide immunization in WT mice exacerbated the EAE symptoms. Adoptive transfer of CD20−/-− CD1d hi CD5+ regulatory B cells before EAE induction completely normalized EAE exacerbated by treatment with anti-CD20 mAb, indicating the therapeutic potency of regulatory B cells in a mouse MS model. Interestingly, B cell depletion using anti-CD20 mAb after the establishment of the disease (on day 14) ameliorated the disease symptoms in contrast to depletion before EAE induction, and the adoptive transfer of regulatory B cells did not suppress established EAE., By contrast, regulatory T cell depletion after onset of EAE worsened late-phase disease. Thereby, regulatory B cells regulate the effector subsets during disease initiation, whereas regulatory T cells are mainly involved in the regulation of the late phase of the disease.
The first study about IL-10 production by peripheral blood B cells from MS patients was reported in 2007. Duddy et al. showed that IL-10 production from B cells in both relapsing-remitting MS and secondary progressive MS patients was significantly decreased compared with those in normal controls when PBMC were cultured with CD40L in the presence or absence of anti-human IgG and IgM polyclonal antibody for 48 h, which was corrected by mitoxantrone treatment. Another study also showed reduction of IL-10 production from B cells in MS patients when incubated with CpG for 24 h. A different study demonstrated that frequency of IL-10+ B cells in patients with relapsing-remitting MS significantly decreased compared with those in normal controls, when PBMC were cultured with CpG for 72 h with the additional PMA and ionomycin.
Collectively, IL-10 production and regulatory function of peripheral blood B cells are impaired in MS patients. Manipulating regulatory function of B cells can be a novel therapeutic approach for the treatment of MS.
Inflammatory bowel disease (IBD) is a chronic relapsing intestinal inflammatory disease, which is mediated by both common and distinct mechanisms with different clinical features.,, The prevalence and incidence of IBD are increasing with time and in different regions around the world. B cells have been generally considered to play a pathogenic role in IBD  because increased production of anti-goblet cell autoantibodies was associated with IBD, especially UC. However, Mizoguchi et al. showed a protective role of B cells and autoantibodies in T cell receptor (TCR) α chain-deficient (TCR α-/-) mice, which spontaneously developed chronic colitis. They subsequently demonstrated that CD1d + B cells were induced in gut-associated lymphoid tissues of mice with intestinal inflammation and dampened the disease symptoms via IL-10 production in TCR α-/-mice. In addition, in TCR α-/-mice, IL-10-producing B cells also suppressed Th2-mediated intestinal inflammation through induction of IL-12-producing B cells.
The efficacy of adoptive transfer of B cells from mesenteric lymph nodes was demonstrated in G protein α inhibitory subunit 2-deficient mice, another spontaneous model of IBD., CD1d hi CD5+ regulatory B cells from spleen or peritoneal cavity have also been demonstrated to have suppressive activity in different mouse colitis models such as dextran sodium sulfate-induced acute colitis., CD1d hi CD5+ regulatory B cells control the intestinal inflammation by decreasing IFN-γ-producing T cells and increasing regulatory T cells., Recently, IL-10-producing B cells with remarkable phenotypes were identified in IL-33-treated mice, and their adoptive transfer blocked the development of colitis in IL-10-/-mice.
Collectively, regulatory B cells play an important role in the suppression of intestinal inflammation and ameliorate disease manifestations in IBD mouse models in an IL-10-dependent manner.
Other studies have shown that B cells isolated from helminth-infected mice have a protective function in allergy by controlling fatal anaphylaxis or ovalbumin-induced airway inflammation via IL-10 production.,,,
In clinical research, several reports show that regulatory B cell dysfunction is involved in human diseases and regulatory B cells play an important role in preventing the disease onset or suppressing the disease symptoms. Clarifying more details of the immune regulation by human regulatory B cells could provide a basis for the development of novel B cell-mediated therapeutic strategies.
| Conclusion|| |
The past decade has provided striking new insights into the diverse phenotypic and functional subsets of regulatory B cells. The different diseases resulting from disruption of regulatory B cell homeostasis emphasize the importance of immunosuppressive regulatory B cells. Although the functions and signaling pathways of Breg cells are intensively studied, many parts of these remain unclear. We investigate a novel phenotypic marker and signaling mechanisms of Breg cells using microarray analysis. Microarray analysis revealed some significant pathways including PI3K-Akt pathway and markers for IL-10 production in B cells. Furthermore, the inhibition of these pathways reduced IL-10 production in B cells and Breg cells were significantly increased in B cell-specific knock-out mice, which exhibits aberrant activation of these pathways in B cells. Signal transduction mediated by IFNs is emerging as another valuable inducer of regulatory B cells; IFNs are essential cytokines for host innate immune responses against viral infections, and they enable B cells to modulate humoral immunity through immunoglobulin class-switch recombination and plasma cell differentiation in mice and humans. IFNs do not drive IL-10 expression directly, but that they can amplify TLR-mediated IL-10 production in part due to increased expression of MyD88, a TLR signaling adapter molecule. Given that IFNs are involved in the pathogenesis of human autoimmune diseases, such inflammatory conditions may induce not only autoantibody-secreting plasma cells, but also IL-10-producing regulatory plasmablasts to inhibit excess inflammation. Further investigation into regulatory B cell biology and the signals that drive regulatory B cell differentiation could provide ways of reshaping and resetting the immune system for better treatment of various immune-related pathologies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hall BM, Pearce NW, Gurley KE, Dorsch SE. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action. J Exp Med 1990;171:141-57.
Li XC, Turka LA. An update on regulatory T cells in transplant tolerance and rejection. Nat Rev Nephrol 2010;6:577-83.
Wieckiewicz J, Goto R, Wood KJ. T regulatory cells and the control of alloimmunity: From characterisation to clinical application. Curr Opin Immunol 2010;22:662-8.
Shevach EM. Regulatory T cells in autoimmmunity. Annu Rev Immunol 2000;18:423-49.
Sakaguchi S. Regulatory T cells: Key controllers of immunologic self-tolerance. Cell 2000;101:455-8.
Furtado GC, Olivares-Villago GC D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ. Regulatory T cells in spontaneous autoimmune encephalomyelitis. Immunol Rev 2001;182:122-34.
Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184:387-96.
Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, et al.
B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000;12:431-40.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-6.
Hori S, Nomura T, Sakaguchi S. Pillars article: Control of regulatory T cell development by the transcription factor foxp3. Science 2003. 299: 1057-1061.
Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4:337-42.
Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531-62.
Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004;4:665-74.
Mauri C, Blair PA. Regulatory B cells in autoimmunity: Developments and controversies. Nat Rev Rheumatol 2010;6:636-43.
Homann D, Tishon A, Berger DP, Weigle WO, von Herrath MG, Oldstone MB. Evidence for an underlying CD4 helper and CD8 T-cell defect in B-cell-deficient mice: Failure to clear persistent virus infection after adoptive immunotherapy with virus-specific memory cells from muMT/muMT mice. J Virol 1998;72:9208-16.
Bergmann CC, Ramakrishna C, Kornacki M, Stohlman SA. Impaired T cell immunity in B cell-deficient mice following viral central nervous system infection. J Immunol 2001;167:1575-83.
O'Neill SK, Cao Y, Hamel KM, Doodes PD, Hutas G, Finnegan A. Expression of CD80/86 on B cells is essential for autoreactive T cell activation and the development of arthritis. J Immunol 2007;179:5109-16.
Linton PJ, Bautista B, Biederman E, Bradley ES, Harbertson J, Kondrack RM, et al.
Costimulation via OX40L expressed by B cells is sufficient to determine the extent of primary CD4 cell expansion and Th2 cytokine secretion in vivo
. J Exp Med 2003;197:875-83.
DiLillo DJ, Matsushita T, Tedder TF. B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N
Y Acad Sci 2010;1183:38-57.
Fillatreau S. Novel regulatory functions for toll-like receptor-activated B cells during intracellular bacterial infection. Immunol Rev 2011;240:52-71.
Mauri C. Regulation of immunity and autoimmunity by B cells. Curr Opin Immunol 2010;22:761-7.
Vitale G, Mion F, Pucillo C. Regulatory B cells: Evidence, developmental origin and population diversity. Mol Immunol 2010;48:1-8.
Katz SI, Parker D, Turk JL. B-cell suppression of delayed hypersensitivity reactions. Nature 1974;251:550-1.
Neta R, Salvin SB. Specific suppression of delayed hypersensitivity: The possible presence of a suppressor B cell in the regulation of delayed hypersensitivity. J Immunol 1974;113:1716-25.
Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med 1996;184:2271-8.
Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med 1997;186:1749-56.
Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 2002;16:219-30.
Ono S, Shao D, Yamada S, Yang Y, Yamashita M, Hamaoka T. A novel function of B lymphocytes from normal mice to suppress autoimmunity in (NZB x NZW)F1 mice. Immunology 2000;100:99-109.
Tian J, Zekzer D, Hanssen L, Lu Y, Olcott A, Kaufman DL. Lipopolysaccharide-activated B cells down-regulate th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. J Immunol 2001;167:1081-9.
Matsushita T, Fujimoto M, Hasegawa M, Komura K, Takehara K, Tedder TF, et al.
Inhibitory role of CD19 in the progression of experimental autoimmune encephalomyelitis by regulating cytokine response. Am J Pathol 2006;168:812-21.
Watanabe R, Fujimoto M, Ishiura N, Kuwano Y, Nakashima H, Yazawa N, et al.
CD19 expression in B cells is important for suppression of contact hypersensitivity. Am J Pathol 2007;171:560-70.
Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, et al.
Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol 2007;178:7868-78.
Tedder TF. B10 cells: A functionally defined regulatory B cell subset. J Immunol 2015;194:1395-401.
Lykken JM, Candando KM, Tedder TF. Regulatory B10 cell development and function. Int Immunol 2015;27:471-7.
Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhiCD5+phenotype controls T cell-dependent inflammatory responses. Immunity 2008;28:639-50.
Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol 2009;182:7459-72.
Maseda D, Candando KM, Smith SH, Kalampokis I, Weaver CT, Plevy SE, et al.
Peritoneal cavity regulatory B cells (B10 cells) modulate IFN-ing IL-10 (B10 cells) requires antigen receptor diversity anImmunol 2013;191:2780-95.
Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, 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;121:3645-56.
Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al.
Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood 2011;117:530-41.
Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, et al.
Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol 2007;178:6092-9.
Blair PA, Norer LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al.
CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity 2010;32:129-40.
Matsushita T, Tedder TF. Identifying regulatory B cells (B10 cells) that produce IL-10 in mice. Methods Mol Biol 2011;677:99-111.
Lampropoulou V, Hoehlig K, Roch T, Neves P, Calderld GlderlderSweenie CH, et al.
TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol 2008;180:4763-73.
Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002;3:944-50.
Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10-producing B cells. J Exp Med 2003;197:489-501.
Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol 2002;3:944.
Lampropoulou V, Calderon-Gomez E, Roch T, Neves P, Shen P, Stervbo U, et al.
Suppressive functions of activated B cells in autoimmune diseases reveal the dual roles of toll-like receptors in immunity. Immunol Rev 2010;233:146-61.
Saraiva M, O'Garra A. The regulation of IL-10 production by immune cells. Nat Rev Immunol 2010;10:170-81.
Duddy ME, Alter A, Bar-Or A. Distinct profiles of human B cell effector cytokines: A role in immune regulation? J Immunol 2004;172:3422-7.
Baba Y, Kurosaki T. Impact of Ca2+ signaling on B cell function. Trends Immunol 2011;32:589-94.
Baba Y, Kurosaki T. Physiological function and molecular basis of STIM1-mediated calcium entry in immune cells. Immunol Rev 2009;231:174-88.
Hogan PG, Lewis RS, Rao A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 2010;28:491-533.
Matsumoto M, Fujii Y, Baba A, Hikida M, Kurosaki T, Baba Y. The calcium sensors STIM1 and STIM2 control B cell regulatory function through interleukin-10 production. Immunity 2011;34:703-14.
Jin G, Hamaguchi Y, Matsushita T, Hasegawa M, Le Huu D, Ishiura N, et al.
B-cell linker protein expression contributes to controlling allergic and autoimmune diseases by mediating IL-10 production in regulatory B cells. J Allergy Clin Immunol 2013;131:1674-82.
Ghosh S, Koralov SB, Stevanovic I, Sundrud MS, Sasaki Y, Rajewsky K, et al.
Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 2010;107:15169-74.
Greenblatt MB, Aliprantis A, Hu B, Glimcher LH. Calcineurin regulates innate antifungal immunity in neutrophils. J Exp Med 2010;207:923-31.
Bhattacharyya S, Deb J, Patra AK, Thuy Pham DA, Chen W, Vaeth M, et al.
NFATc1 affects mouse splenic B cell function by controlling the calcineurin alcFAT signaling network. J Exp Med 2011;208:823-39.
Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, et al.
Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity 2014;41:1040-51.
Villagra A, Cheng F, Wang HW, Suarez I, Glozak M, Maurin M, et al.
The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance. Nat Immunol 2009;10:92-100.
Macian F. NFAT proteins: Key regulators of T-cell development and function. Nat Rev Immunol 2005;5:472-84.
Haas KM, Watanabe R, Matsushita T, Nakashima H, Ishiura N, Okochi H, et al.
Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. J Immunol 2010;184:4789-800.
Watanabe R, Ishiura N, Nakashima H, Kuwano Y, Okochi H, Tamaki K, et al.
Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol 2010;184:4801-9.
Teichmann LL, Kashgarian M, Weaver CT, Roers A, M A, M CT, Shlomchik MJ. B cell-derived IL-10 does not regulate spontaneous systemic autoimmunity in MRL. Fas(lpr) mice. J Immunol 2012;188:678-85.
Blair PA, Chavez-Rueda KA, Evans JG, Shlomchik MJ, Eddaoudi A, Isenberg DA, et al.
Selective targeting of B cells with agonistic anti-CD40 is an efficacious strategy for the generation of induced regulatory T2-like B cells and for the suppression of lupus in MRL/lpr mice. J Immunol 2009;182:3492-502.
Amel Kashipaz MR, Huggins ML, Lanyon P, Robins A, Powell RJ, Todd I. Assessment of Be1 and Be2 cells in systemic lupus erythematosus indicates elevated interleukin-10 producing CD5+ B cells. Lupus 2003;12:356-63.
D63.-Alderete A, Crispin JC, Vargas-Rojas MI, Alcocer-Varela J. IL-10 production in B cells is confined to CD154+ cells in patients with systemic lupus erythematosus. J Autoimmun 2004;23:379-83.
Yang X, Yang J, Chu Y, Xue Y, Xuan D, Zheng S, et al.
T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus. PLoS One 2014;9:e88441.
Gao N, Dresel J, Eckstein V, Gellert R, St, St H, Venigalla RK, et al.
Impaired suppressive capacity of activation-induced regulatory B cells in systemic lupus erythematosus. Arthritis Rheumatol 2014;66:2849-61.
Yang M, Deng J, Liu Y, Ko KH, Wang X, Jiao Z, et al.
IL-10-producing regulatory B10 cells ameliorate collagen-induced arthritis via suppressing Th17 cell generation. Am J Pathol 2012;180:2375-85.
Gray M, Miles K, Salter D, Gray D, Savill J. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A 2007;104:14080-5.
Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, et al.
CD19+ CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med 2013;5:173ra23.
Lyons JA, Ramsbottom MJ, Mikesell RJ, Cross AH. B cells limit epitope spreading and reduce severity of EAE induced with PLP peptide in BALB/c mice. J Autoimmun 2008;31:149-55.
Matsushita T, Yanaba K, Bouaziz JD, Fujimoto M, Tedder TF. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression. J Clin Invest 2008;118:3420-30.
Matsushita T, Horikawa M, Iwata Y, Tedder TF. Regulatory B cells (B10 cells) and regulatory T cells have independent roles in controlling experimental autoimmune encephalomyelitis initiation and late-phase immunopathogenesis. J Immunol 2010;185:2240-52.
Hirotani M, Niino M, Fukazawa T, Kikuchi S, Yabe I, Hamada S, et al.
Decreased IL-10 production mediated by toll-like receptor 9 in B cells in multiple sclerosis. J Neuroimmunol 2010;221:95-100.
Knippenberg S, Peelen E, Smolders J, Thewissen M, Menheere P, Cohen Tervaert JW, et al.
Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced nad naclerosiBreg ratio during a relapse but not in remission. J Neuroimmunol 2011;239:80-6.
Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427-34.
Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol 2010;28:573-621.
Talley NJ, Abreu MT, Achkar JP, Bernstein CN, Dubinsky MC, Hanauer SB, et al.
An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 2011;106 Suppl 1:S2-25.
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al.
Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46.
Mombaerts P, Mizoguchi E, Grusby MJ, Glimcher LH, Bhan AK, Tonegawa S. Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice. Cell 1993;75:274-82.
Targan SR, Karp LC. Defects in mucosal immunity leading to ulcerative colitis. Immunol Rev 2005;206:296-305.
Sugimoto K, Ogawa A, Shimomura Y, Nagahama K, Mizoguchi A, Bhan AK. Inducible IL-12-producing B cells regulate Th2-mediated intestinal inflammation. Gastroenterology 2007;133:124-36.
Wei B, Velazquez P, Turovskaya O, Spricher K, Aranda R, Kronenberg M, et al.
Mesenteric B cells centrally inhibit CD4+ T cell colitis through interaction with regulatory T cell subsets. Proc Natl Acad Sci U S A 2005;102:2010-5.
Yanaba K, Yoshizaki A, Asano Y, Kadono T, Tedder TF, Sato S. IL-10-producing regulatory B10 cells inhibit intestinal injury in a mouse model. Am J Pathol 2011;178:735-43.
Schmidt EG, Larsen HL, Kristensen NN, Poulsen SS, Claesson MH, Pedersen AE. B cells exposed to enterobacterial components suppress development of experimental colitis. Inflamm Bowel Dis 2012;18:284-93.
Sattler S, Ling GS, Xu D, Hussaarts L, Romaine A, Zhao H, et al.
IL-10-producing regulatory B cells induced by IL-33 (Breg (IL-33)) effectively attenuate mucosal inflammatory responses in the gut. J Autoimmun 2014;50:107-22.
Mangan NE, Fallon RE, Smith P, van Rooijen N, McKenzie AN, Fallon PG. Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 2004;173:6346-56.
Mangan NE, van Rooijen N, McKenzie AN, Fallon PG. Helminth-modified pulmonary immune response protects mice from allergen-induced airway hyperresponsiveness. J Immunol 2006;176:138-47.
Amu S, Saunders SP, Kronenberg M, Mangan NE, Atzberger A, Fallon PG. Regulatory B cells prevent and reverse allergic airway inflammation via foxP3-positive T regulatory cells in a murine model. J Allergy Clin Immunol 2010;125:1114-24.
van der Vlugt LE, Labuda LA, Ozir-Fazalalikhan A, Lievers E, Gloudemans AK, Liu KY, et al.
Schistosomes induce regulatory features in human and mouse CD1d (hi) B cells: Inhibition of allergic inflammation by IL-10 and regulatory T cells. PLoS One 2012;7:e30883.