Gut-derived acetate promotes B10 cells with antiinflammatory effects.

Autoimmune diseases are characterized by a breakdown of immune tolerance partly due to environmental factors. The short-chain fatty acid acetate, derived mostly from gut microbial fermentation of dietary fiber, promotes antiinflammatory Tregs and protects mice from type 1 diabetes, colitis, and allergies. Here, we show that the effects of acetate extend to another important immune subset involved in tolerance, the IL-10-producing regulatory B cells (B10 cells). Acetate directly promoted B10 cell differentiation from mouse B1a cells both in vivo and in vitro. These effects were linked to metabolic changes through the increased production of acetyl-coenzyme A, which fueled the TCA cycle and promoted posttranslational lysine acetylation. Acetate also promoted B10 cells from human blood cells through similar mechanisms. Finally, we identified that dietary fiber supplementation in healthy individuals was associated with increased blood-derived B10 cells. Direct delivery of acetate or indirect delivery via diets or bacteria that produce acetate might be a promising approach to restore B10 cells in noncommunicable diseases.

The role of regulatory B cells in Echinococcus granulosus-infected mice.

To investigate the phenotypic changes of the expression level of regulatory B cells and related molecules during the continuous infection of Echinococcus granulosus (E. granulosus) in mice and its relationship with E. granulosus infection and its immune effect. Experimental group mice were inoculated with protoscoleces suspension via intraperitoneally injection to prepare a mouse model of E. granulosus infection. Flow cytometry was used to detect the expression of regulatory B cells CD1dhiCD5+CD19hi cells and CD1dhiCD5+CD19hi IL-10+ cells in spleen and peripheral blood of mice. The expressions of IL-10 and TGF-ß1 in mouse serum were detected via ELISA. The liver pathological changes in mice were observed by H&E staining; Moreover, the expressions and distribution of IL-10 and TGF-ß1 in mice liver were measured through immunohistochemistry. The ELISA test results showed no significant changes in serum IL-10 and TGF-ß1 levels in early infected mice. However, at the middle and late stages of infection, the levels of IL-10 and TGF-ß1 in the serum of mice increased significantly (P < 0.05). The proportion of CD1dhiCD5+CD19hiBreg cells and the proportion of CD1dhiCD5+CD19hiIL-10+Breg cells in the spleen of mice infected with E. granulosus were increased at 90 days after infection, which indicating that Breg cells proliferated in the late stage of infection. CD1dhiCD5+CD19hi regulatory B cells may be one of the causes of immunosuppression of E. granulosus infection. It is speculated that Bregs inhibitory effect may play a role by regulating the expression of cytokines and inducing the secretion of inhibitory cytokines IL-10 and TGF-ß1.

Regulatory B cells in infection, inflammation, and autoimmunity.

Regulatory B (Breg) cells are characterized by differential expression of CD5 and CD1d in mouse and CD24 and CD38 in human immune systems. The Breg family also includes LAG-3+CD138hi plasma cells, CD1d CD5 CD21 CD23 cells, Tim1, PD-L1, PD-L2, CD200- expressing B cells, and CD39hiKi67+ cells originating from the transitional, marginal zone or germinal centre of the spleen. Breg cells produce IL10 and IL35 and to cause immunosuppression. These cells respond to TLR2, TLR4, and TLR9 agonists, CD40 ligands, IL12p35 and heat shock proteins. Emerging evidence suggests that TLR signalling component Myd88 impacts the modulation of Breg cell responses and the host's susceptibility to infection. Breg cells are found to reduce relapsing-remitting experimental autoimmune encephalomyelitis. However, the Breg-mediated mechanism used to control T cell-mediated immune responses is still unclear. Here, we review the existing literature to find gaps in the current knowledge and to build a pathway to further research.

Human chorionic gonadotropin and IL-35 contribute to the maintenance of peripheral immune tolerance during pregnancy through mediating the generation of IL-10+ or IL-35+ Breg cells.

Regulatory B cells (Breg cells) play critical roles in modulating immune responses during autoimmune diseases and infection. Here we explored the participation of two main Breg subsets, including IL-10+ Breg (B10) and IL-35+ Breg cells, in maintaining successful pregnancy. We first observed an elevated percentage of B10 cells in peripheral blood from first-trimester pregnant women compared with non-pregnant controls. Serum from pregnancy induced the augmentation of B10  in peripheral blood mononuclear cells from non-pregnant women. In animal models, we demonstrated that there were significant augmentation of B10 cells and obvious increase of IL-10 level in splenic B cells from normal pregnant mice compared to that in abortion-prone pregnant mice and virgin mice. Further analysis showed that both hCG and IL-35 suppressed the proliferation of mouse splenic B cells. Moreover, IL-35 induced the expansion of both mouse splenic B10 and IL-35+ Breg cells while hCG only mediated the generation of B10 cells. Subsequent study in mice demonstrated that the activation of STAT1 and STAT3 in B cells caused by IL-35 and the activation of STAT3 caused by hCG were the predominant mechanism of IL-35+ Breg and B10 cells augmentation. These findings suggested that hCG and IL-35 induced the amplification of B10 and IL-35+ Breg cells which played a vital peripheral regulatory role during pregnancy.

Natural and inducible regulatory B cells are widely distributed in ovine lymphoid tissues.

Regulatory B cells that produce IL-10 are now recognized as an important component of the immune system. We previously confirmed that IL-10 secreting CD21+ regulatory B cells (Breg cells) were present in ovine jejunal Peyer's patches (JPP) and this IL-10 production suppressed IL-12 and IFN-γ secretion. It is not known, however, whether ovine Breg cells are restricted to JPP or are present in other lymphoid tissues. Therefore, CD21+ B cells were purified from sheep JPP and from a variety of mucosal and systemic lymphoid tissues using magnetic cell sorting. Purified CD21+ B cells were stimulated with a TLR9-agonist, CpG oligodeoxynucleotide (CpG ODN), and the frequency of spontaneous and inducible (i) IL-10-secreting B cells was evaluated by ELISPOT. Spontaneous IL-10 secreting CD21+ B cells were present in mucosal (jejunal PP, parabronchial lymph nodes (LN), mesesnteric LN, and palatine tonsils) and systemic (spleen and blood) lymphoid tissues. Mucosal lymphoid tissues (parabronchial and mesenteric LNs and JPP) had the highest frequency of cells spontaneously secreting IL-10 while tonsils had the lowest. The frequency of B cells spontaneously secreting IL-10 was lowest in blood and spleen. There was large inter-animal variation in the frequency of CD21+ B cells spontaneously secreting IL-10 and no significant difference was detected following CpG ODN stimulation. When comparing within individual animals there was, however, a consistent increase in the frequency of CD21+ cells secreting IL-10 following CpG ODN stimulation versus stimulation with GpC control ODN. The presence of inducible (i)Breg cells in ovine mucosal tissues supports previous evidence from mice indicating that B cells have the capacity to modulate inflammatory responses. The presence of iBreg cells in ruminants may also provide a novel therapeutic target for both immunomodulatory drugs and vaccines designed to control antigen-specific mucosal inflammation.

IL-10-producing B cells are characterized by a specific methylation signature.

Among the family of regulatory B cells, the subset able to produce interleukin-10 (IL-10) is the most studied, yet its biology is still a matter of investigation. The DNA methylation profiling of the il-10 gene locus revealed a novel epigenetic signature characterizing murine B cells ready to respond through IL-10 synthesis: a demethylated region located 4.5 kb from the transcription starting site (TSS), that we named early IL10 regulatory region (eIL10rr). This feature allows to distinguish B cells that are immediately prone and developmentally committed to IL-10 production from those that require a persistent stimulation to exert an IL-10-mediated regulatory function. These late IL-10 producers are instead characterized by a delayed IL10 regulatory region (dIL10rr), a partially demethylated DNA portion located 9 kb upstream from the TSS. A demethylated region was also found in human IL-10-producing B cells and, very interestingly, in some B-cell malignancies, such as chronic lymphocytic leukemia and mantle cell lymphoma, characterized by an immunosuppressive microenvironment. Our findings define murine and human regulatory B cells as an epigenetically controlled functional state of mature B cell subsets and open a new perspective on IL-10 regulation in B cells in homeostasis and disease.

Regulatory and Effector B Cells: A New Path Toward Biomarkers and Therapeutic Targets to Improve Transplant Outcomes?

B cells shape the alloimmune response through polarized subsets. These cells inhibit or promote immune responses by expressing suppressive or proinflammatory cytokines. Their summed activity dictates the influence of B cells on the alloimmune response. We review the evidence for regulatory B cells and effector B cells in mice and humans, discuss current limitations in their phenotypic identification, and discuss regulatory B cells as a signature for clinical renal allograft tolerance and predictive markers for allograft outcomes. We discuss the effects of therapeutic agents on regulatory B cells and potential approaches to augment their numbers as a therapeutic tool.

Regulatory B cells in inflammatory diseases and tumor.

As antigen-presenting cells (APC), B cells exert a variety of immune regulatory functions mainly by presenting antigens, triggering immune response, and producing antibodies for immune regulation. Regulatory B cells (Bregs) are special subpopulations of B cells with immune-regulating or immune-suppressing properties and play a role in peripheral tolerance. Bregs suppress immune response through inhibiting the differentiation of dendritic cells (DCs), suppressing the proliferation of helper T1(TH1) cells and helper T17 (TH17) cells, inducing the differentiation of fork head transcription factor p3 positive regulatory T cells (FoxP3+ Tregs). Different subsets of Bregs have distinct phenotypes and markers. Different subsets of Bregs participate in immune modulation by different ways. The absence or loss of Bregs exacerbates the severity of many disease such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and graft-versus-host-disease (GVHD). Bregs are also involved in tumor immunosuppressive effect and inhibit the antitumor immune process. In this article, we review the research advances of Bregs in autoimmune diseases, GVHD and tumor.

Promises and limitations of immune cell-based therapies in neurological disorders.

The healthy immune system has natural checkpoints that temper pernicious inflammation. Cells mediating these checkpoints include regulatory T cells, regulatory B cells, regulatory dendritic cells, microglia, macrophages and monocytes. Here, we highlight discoveries on the beneficial functions of regulatory immune cells and their mechanisms of action and evaluate their potential use as novel cell-based therapies for brain disorders. Regulatory immune cell therapies have the potential not only to mitigate the exacerbation of brain injury by inflammation but also to promote an active post-injury brain repair programme. By harnessing the reparative properties of these cells, we can reduce over-reliance on medications that mask clinical symptoms but fail to impede or reverse the progression of brain disorders. Although these discoveries encourage further testing and genetic engineering of regulatory immune cells for the clinical management of neurological disorders, a number of challenges must be surmounted to improve their safety and efficacy in humans.

Circulating regulatory Tfh cells are enriched in patients with chronic hepatitis B infection and induce the differentiation of regulatory B cells.

Chronic hepatitis B virus (HBV) infection is a complex disease with dysregulations in the immune system. Follicular helper T (Tfh) cells are professional B helper cells that are crucial to the development of antibody responses and are involved in a variety of diseases. In this study, we examined the circulating Tfh cells in patients with chronic HBV infection. We observed that CD3+CD4+CXCR5+ circulating Tfh cells contained a CD25+Foxp3+ Treg-like subset that was significantly enriched in patients with chronic HBV infections. The CD25+ Tfh subset presented distinctive cytokine secretion profile, such as lower interferon (IFN)-γ and interleukin (IL)-17, and higher transforming growth factor (TGF)-ß secretion, compared to the CD25- Tfh subset. When incubated with autologous naive CD10-CD27-CD19+ B cells, the CD25+ Tfh subset was less capable of mediating CD20-/loCD38+ plasmablast differentiation than the CD25- Tfh subset. In terms of Ig production, CD25+ Tfh cells were more potent at inducing IgM but less potent at inducing IgG and IgA than CD25- Tfh cells. Interestingly, B cells following incubation with CD25+ Tfh cells presented elevated regulatory function, with higher production of IL-10 and enhanced capacity of suppressing autologous CD8+ T cell inflammation. In the chronic HBV-infected patients, the frequency of IL-10+ B cells and the HBV viral load were positively correlated with the frequency of CD25+Foxp3+ CD4+CXCR5+ Tfh cells. Together, this study presented that CD25+Foxp3+ Treg-like Tfh cells were enriched in chronic HBV-infected patients and could promote regulatory B cell functions.

[Regulatory B cells (Bregs) role in allergic diseases]. / Participación de los linfocitos B reguladores (Breg) en las enfermedades alérgicas.

Immune tolerance, both to exogenous antigens and autoantigens, is essential for restraining undesired inflammatory responses that might result in severe damage to body tissues or cause chronic diseases. During the past few decades, different cell populations and molecules by them secreted have been associated with suppressing and regulatory mechanisms of immune responses. Although B cells typically acquire relevance as precursors of antibody-producing cells, they can also develop potent regulatory functions through the production of soluble molecules or by establishing direct cellular interactions mediated by different surface proteins implicated in signal transduction. While most studies of regulatory B cells define the role of these lymphocytes in autoimmune diseases, evidence of their importance and mechanisms of action in allergic diseases has accumulated in recent years. As a result, regulatory B cells appear to be relevant elements for the establishment or loss of allergen tolerance in different allergic diseases, although they still have been little explored.

La tolerancia inmunológica, tanto a los antígenos exógenos como a los autoantígenos, es esen-cial para restringir las respuestas inflamatorias no deseadas que pudieran derivar en daño grave a los tejidos del organismo o provocar enfermedades crónicas. Durante las últimas décadas, diversas poblaciones celulares y moléculas secretadas por estas se han asociado con mecanismos supresores y reguladores de las respuestas inmunes. Aunque las células B adquieren relevancia típicamente como precursores de células productoras de anticuerpos, también son capaces desarrollar potentes funciones reguladoras a través de la producción de moléculas solubles o mediante el establecimiento de interacciones celulares directas mediadas por diferentes proteínas de superficie implicadas en transducción de señales. Si bien la mayoría de los estudios de células B reguladoras definen el papel de estos linfocitos en enfermedades autoinmunes, en años recientes se ha acumulado evidencia de su importancia y mecanismos de acción en enfer-medades alérgicas. Las células reguladoras B parecen ser elementos relevantes en el establecimiento o pérdida de la tolerancia a alérgenos en diferentes enfermedades alérgicas, si bien aún han sido poco explorados.

Pathogenic Correlates of Simian Immunodeficiency Virus-Associated B Cell Dysfunction.

We compared and contrasted pathogenic (in pig-tailed macaques [PTMs]) and nonpathogenic (in African green monkeys [AGMs]) SIVsab infections to assess the significance of the B cell dysfunction observed in simian (SIV) and human immunodeficiency virus (HIV) infections. We report that the loss of B cells is specifically associated with the pathogenic SIV infection, while in the natural hosts, in which SIV is nonpathogenic, B cells rapidly increase in both lymph nodes (LNs) and intestine. SIV-associated B cell dysfunction associated with the pathogenic SIV infection is characterized by loss of naive B cells, loss of resting memory B cells due to their redistribution to the gut, increases of the activated B cells and circulating tissue-like memory B cells, and expansion of the B regulatory cells (Bregs). While circulating B cells are virtually restored to preinfection levels during the chronic pathogenic SIV infection, restoration is mainly due to an expansion of the "exhausted," virus-specific B cells, i.e., activated memory cells and tissue-like memory B cells. Despite of the B cell dysfunction, SIV-specific antibody (Ab) production was higher in the PTMs than in AGMs, with the caveat that rapid disease progression in PTMs was strongly associated with lack of anti-SIV Ab. Neutralization titers and the avidity and maturation of immune responses did not differ between pathogenic and nonpathogenic infections, with the exception of the conformational epitope recognition, which evolved from low to high conformations in the natural host. The patterns of humoral immune responses in the natural host are therefore more similar to those observed in HIV-infected subjects, suggesting that natural hosts may be more appropriate for modeling the immunization strategies aimed at preventing HIV disease progression. The numerous differences between the pathogenic and nonpathogenic infections with regard to dynamics of the memory B cell subsets point to their role in the pathogenesis of HIV/SIV infections and suggest that monitoring B cells may be a reliable approach for assessing disease progression.IMPORTANCE We report here that the HIV/SIV-associated B cell dysfunction (defined by loss of total and memory B cells, increased B regulatory cell [Breg] counts, and B cell activation and apoptosis) is specifically associated with pathogenic SIV infection and absent during the course of nonpathogenic SIV infection in natural nonhuman primate hosts. Alterations of the B cell population are not correlated with production of neutralizing antibodies, the levels of which are similar in the two species. Rapid progressive infections are associated with a severe impairment in SIV-specific antibody production. While we did not find major differences in avidity and maturation between the pathogenic and nonpathogenic SIV infections, we identified a major difference in conformational epitope recognition, with the nonpathogenic infection being characterized by an evolution from low to high conformations. B cell dysfunction should be considered in designing immunization strategies aimed at preventing HIV disease progression.

Interleukin 35 Rescues Regulatory B Cell Function, but the Effect Is Dysregulated in Ulcerative Colitis.

Ulcerative colitis (UC) is a long-time inflammatory condition arising from aberrant immune activation in the colon and the rectum. Interleukin (IL)-35 plays critical roles in autoimmune disorders. In this study, we explored the pathways of IL-35 in affecting UC. First, peripheral blood mononuclear cells (PBMCs) from UC patients were obtained. Pretreating PBMCs with IL-35 resulted in significantly elevated IL-10 production from whole PBMCs as well as B cells, whereas pretreating PBMCs with IL-12 or IL-27 did not demonstrate a similar effect. IL-35 suppressed the proliferation of CD4+CD25- conventional T cells, CD4+CD25+ regulatory T (Treg) cells, and CD8+ T cells, but did not inhibit the proliferation of B cells. IL-35-mediated IL-10 secretion in B cells did not require the presence of Treg cells. After treatment with IL-35, B cells from UC patients presented significantly enhanced regulatory function, characterized by inhibiting cell proliferation and interferon (IFN)-γ, IL-17, and tumor necrosis factor (TNF)-α secretion from autologous CD4+CD25- T cells and CD8+ T cells, which was dependent on IL-10 signaling. However, IL-35-treatment did not demonstrate an effect on regulating IL-5 and IL-13 responses. These discoveries identified a Th1, Th17, and CD8+ T cell-targeting role of IL-35 in UC patients. Next, we examined the IL-35 expression in the intestinal mucosal in UC patients. Data showed that both noninflamed and inflamed tissues from UC patients presented significantly lower IL-35 secretion compared to healthy control tissues, which was associated with suppressed p35 transcription. UC patients with higher IL-35 also presented higher IL-10 secretion in gut mucosa. Together, our study identified that IL-35 could mediate anti-inflammatory function through promoting regulatory B cell functions, but this effect was suppressed in UC patients.

Novel feedback loop between M2 macrophages/microglia and regulatory B cells in estrogen-protected EAE mice.

Immunoregulatory sex hormones, including estrogen and estriol, may prevent relapses in multiple sclerosis during pregnancy. Our previous studies have demonstrated that regulatory B cells are crucial for estrogen-mediated protection against experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of alternatively activated (M2) macrophages/microglia that results in an increased frequency of regulatory B cells in the spinal cord of estrogen treated mice with EAE. We further demonstrate that cultured M2-polarized microglia promote the induction of regulatory B cells. Our study suggests that estrogen neuroprotection induces a regulatory feedback loop between M2 macrophages/microglia and regulatory B cells.

The Regulatory B Cell Compartment Expands Transiently During Childhood and Is Contracted in Children With Autoimmunity.

OBJECTIVE: Regulatory B cells that inhibit immune responses through interleukin-10 (IL-10) secretion (B10 cells) have been characterized in adult subjects with autoimmune disease. The aim of this study was to characterize B10 cells in individuals across the entire age range of normal human development and changes in their frequency and numbers in children with autoimmunity. METHODS: The phenotype and numbers of B10 cells in blood were examined in healthy individuals and children with autoimmunity, using flow cytometry. B10 cell function was assessed by measuring the effect of B cell-derived IL-10 on interferon-γ (IFNγ) expression by CD4+ T cells. Serum cytokine levels were measured by enzyme-linked immunosorbent assay. RESULTS: The frequency of B10 cells transiently increased during childhood, when up to 30% of B cells were competent to produce IL-10, compared with the low frequencies in healthy newborns (3-4%) and adults (7-9%). The surface phenotype of B10 cells in children revealed age-dependent variability. B10 cells from children were distinct from proinflammatory cytokine-producing B cells and down-regulated IFNγ production by CD4+ T cells in vitro. Compared with age-matched healthy controls, children with autoimmunity had lower numbers and frequencies of B10 cells (decreased by 39% and 48%, respectively), higher IFNγ levels, and lower IL-21 levels in serum. IFNγ inhibited, whereas IL-21 promoted, B cell IL-10 competence in vitro. CONCLUSION: B10 cells, a functionally defined cell subset with a variable surface phenotype reflective of overall B cell development, transiently expand during childhood. B10 cell frequencies and numbers were decreased in children with autoimmunity, which may be explained in part by alterations in serum IFNγ and IL-21 that differentially regulate B10 cell development.

B cell subsets are modulated during allergic airway inflammation but are not required for the development of respiratory tolerance in a murine model.

Allergic asthma is a widespread chronic inflammatory disease of the airways. The role of different B cell subsets in developing asthma and respiratory tolerance is not well known. Especially regulatory B (Breg) cells are proposed to be important in asthma regulation. Using wild-type (WT) and B cell-deficient (µMT) mice we investigated how B cells are affected by induction of allergic airway inflammation and respiratory tolerance and whether they are necessary to develop these conditions. WT mice with an asthma-like phenotype, characterized by increased airway hyper reactivity, eosinophilic airway inflammation, mucus hypersecretion and elevated Th2 cytokines, exhibited increased MHCII and CD23 expression on follicular mature B cells in lung, bronchial lymph nodes (bLN) and spleen, which contributed to allergen-specific T cell proliferation in vitro. Germinal center B cell numbers were elevated and associated with increased production of allergen-specific immunoglobulins especially in bLN. In contrast, respiratory tolerance clearly attenuated these B cell alterations and directly enhanced marginal zone precursor B cells, which induced regulatory T cells in vitro. However, µMT mice developed asthma-like and tolerized phenotypes like WT mice. Our data indicate that although B cell subsets are affected by asthma-like and respiratory tolerant phenotypes, B cells are not required for tolerance induction.

Human regulatory B cells control the TFH cell response.

BACKGROUND: Follicular helper T (TFH) cells support terminal B-cell differentiation. Human regulatory B (Breg) cells modulate cellular responses, but their control of TFH cell-dependent humoral immune responses is unknown. OBJECTIVE: We sought to assess the role of Breg cells on TFH cell development and function. METHODS: Human T cells were polyclonally stimulated in the presence of IL-12 and IL-21 to generate TFH cells. They were cocultured with B cells to induce their terminal differentiation. Breg cells were included in these cultures, and their effects were evaluated by using flow cytometry and ELISA. RESULTS: B-cell lymphoma 6, IL-21, inducible costimulator, CXCR5, and programmed cell death protein 1 (PD-1) expressions increased on stimulated human T cells, characterizing TFH cell maturation. In cocultures they differentiated B cells into CD138+ plasma and IgD-CD27+ memory cells and triggered immunoglobulin secretions. Breg cells obtained by Toll-like receptor 9 and CD40 activation of B cells prevented TFH cell development. Added to TFH cell and B-cell cocultures, they inhibited B-cell differentiation, impeded immunoglobulin secretions, and expanded Foxp3+CXCR5+PD-1+ follicular regulatory T cells. Breg cells modulated IL-21 receptor expressions on TFH cells and B cells, and their suppressive activities involved CD40, CD80, CD86, and intercellular adhesion molecule interactions and required production of IL-10 and TGF-ß. CONCLUSION: Human Breg cells control TFH cell maturation, expand follicular regulatory T cells, and inhibit the TFH cell-mediated antibody secretion. These novel observations demonstrate a role for the Breg cell in germinal center reactions and suggest that deficient activities might impair the TFH cell-dependent control of humoral immunity and might lead to the development of aberrant autoimmune responses.

Regulatory B Cells Induce Formation of IL-10-Expressing T Cells in Mice with Autoimmune Neuroinflammation.

Although B cells are traditionally known for their role in propagating proinflammatory immune responses, their immunosuppressive effects have only recently begun to be appreciated. How these regulatory B cells (Bregs) suppress the immune response remains to be worked out in detail. In this article, we show that Bregs can induce the formation of conventional FoxP3+ regulatory T cells (Tregs), as well as a more recently described CD49b+CD223+ regulatory T-cell subset, known as type 1 regulatory T cells (Tr1s). When Bregs are transferred into mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, they home to the spleen and mesenteric lymph nodes, leading to an expansion of Tregs and Tr1 in vivo Tregs and Tr1s are also found in greater proportions in the CNS of mice with EAE treated with Bregs and are correlated with the remission of symptoms. The discovery that Bregs induce the formation of regulatory T-cell subsets in vivo may herald their use as immunosuppressive agents in adoptive cellular therapies for autoimmune pathologies. SIGNIFICANCE STATEMENT: Although B cells are traditionally known for their role in propagating proinflammatory immune responses, their immunosuppressive effects have only recently begun to be appreciated. How regulatory B cells (Bregs) suppress the immune response remains to be fully understood. In this article, we show that Bregs can induce the formation of conventional regulatory T cells (Tregs) as well as type 1 regulatory T cells (Tr1s). When Bregs are transferred into mice with experimental autoimmune encephalomyelitis (EAE), they home to secondary lymphoid organs, leading to an expansion of Tregs and Tr1s in vivo Tregs and Tr1s are also found in greater proportions in the CNS of mice with EAE treated with Bregs and are correlated with the remission of symptoms.

Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells.

The influence of signals perceived by immature B cells during their development in bone marrow on their subsequent functions as mature cells are poorly defined. Here, we show that bone marrow cells transiently stimulated in vivo or in vitro through the Toll-like receptor 9 generate proB cells (CpG-proBs) that interrupt experimental autoimmune encephalomyelitis (EAE) when transferred at the onset of clinical symptoms. Protection requires differentiation of CpG-proBs into mature B cells that home to reactive lymph nodes, where they trap T cells by releasing the CCR7 ligand, CCL19, and to inflamed central nervous system, where they locally limit immunopathogenesis through interleukin-10 production, thereby cooperatively inhibiting ongoing EAE. These data demonstrate that a transient inflammation at the environment, where proB cells develop, is sufficient to confer regulatory functions onto their mature B-cell progeny. In addition, these properties of CpG-proBs open interesting perspectives for cell therapy of autoimmune diseases.