Immune response and treatment targets of chronic hepatitis B virus infection: innate and adaptive immunity.

Chronic hepatitis B virus (HBV) infection is a major global public health risk that threatens human life and health, although the number of vaccinated people has increased. The clinical outcome of HBV infection depends on the complex interplay between viral replication and the host immune response. Innate immunity plays an important role in the early stages of the disease but retains no long-term immune memory. However, HBV evades detection by the host innate immune system through stealth. Therefore, adaptive immunity involving T and B cells is crucial for controlling and clearing HBV infections that lead to liver inflammation and damage. The persistence of HBV leads to immune tolerance owing to immune cell dysfunction, T cell exhaustion, and an increase in suppressor cells and cytokines. Although significant progress has been made in HBV treatment in recent years, the balance between immune tolerance, immune activation, inflammation, and fibrosis in chronic hepatitis B remains unknown, making a functional cure difficult to achieve. Therefore, this review focuses on the important cells involved in the innate and adaptive immunity of chronic hepatitis B that target the host immune system and identifies treatment strategies.

STING-induced regulatory B cells compromise NK function in cancer immunity.

An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers1-3. Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression4. Although these agonists hold promise as potential cancer therapies5, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear5-7. Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35+ regulatory B cells in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING-IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours.

Roles of regulatory B cells in the pathogenesis of allergic rhinitis

Allergic rhinitis (AR) is a common otolaryngologic disease with frequent episodes of sneezing, clear nasal discharge flow and nasal congestion. The mechanisms of AR are complex and considered generally caused by the immune tolerance deficiency. Regulatory B cells (Bregs) are immunosuppressive cells that can modulate immune responses by the secretion of IL-10, IL-35, and tumor growth factor-β (TGF-β) and via the interaction of membrane surface molecules. However, Bregs are numerically deficient and/or dysfunctional in airway allergic diseases such as AR and allergic asthma, and the related mechanisms remain unclear. In this review, we summarize the role of Bregs in AR pathogenesis and highlight the importance of Bregs in maintaining immune tolerance. It is believed that further research on Bregs will contribute to developing new treatments and finding specific biomarkers that could help to predict disease progression (AU)

Enriched circulating and tumor-resident TGF-ß+ regulatory B cells in patients with melanoma promote FOXP3+ Tregs.

B cells are emerging as key players of anti-tumor adaptive immune responses. We investigated regulatory and pro-inflammatory cytokine-expressing B cells in patients with melanoma by flow cytometric intracellular cytokine, CyTOF, transcriptomic, immunofluorescence, single-cell RNA-seq, and B:T cell co-culture analyses. We found enhanced circulating regulatory (TGF-ß+ and PD-L1+) and reduced pro-inflammatory TNF-α+ B cell populations in patients compared with healthy volunteers (HVs), including lower IFN-γ+:IL-4+ and higher TGF-ß+:TNF-α+ B cell ratios in patients. TGF-ß-expressing B cells in the melanoma tumor microenvironment assembled in clusters and interacted with T cells via lymphoid recruitment (SELL, CXCL13, CCL4, CD74) signals and with Tregs via CD47:SIRP-γ, and FOXP3-promoting Galectin-9:CD44. While reduced in tumors compared to blood, TNF-α-expressing B cells engaged in crosstalk with Tregs via TNF-α signaling and the ICOS/ICOSL axis. Patient-derived B cells promoted FOXP3+ Treg differentiation in a TGF-ß-dependent manner, while sustaining expression of IFN-γ and TNF-α by autologous T-helper cells and promoting T-helper cell proliferation ex vivo, an effect further enhanced with anti-PD-1 checkpoint blockade. Our findings reveal cytokine-expressing B cell compartments skewed toward regulatory phenotypes in patient circulation and melanoma lesions, intratumor spatial localization, and bidirectional crosstalk between B and T cell subsets with immunosuppressive attributes.

CXCL13 as a Novel Immune Checkpoint for Regulatory B Cells and Its Role in Tumor Metastasis.

Tumor metastasis is the primary cause of mortality in patients with cancer. Several chemokines are identified as important mediators of tumor growth and/or metastasis. The level of CXCL13 has been reported to be elevated in serum or tumor tissues in patients, which mainly functions to attract B cells and follicular B helper T cells. However, the role of CXCL13 in cancer growth and metastasis is not fully explored. In the current study, we found that CXCL13 is not a strong mediator to directly promote tumor growth; however, the mice deficient in CXCL13 had far fewer pulmonary metastatic foci than did the wild-type mice in experimental pulmonary metastatic models. In addition, Cxcl13 -/- mice also had fewer IL-10-producing B cells (CD45+CD19+IL-10+) in the metastatic tumor immune microenvironment than those of wild-type C57BL/6 mice, resulting in an enhanced antitumor immunity. Notably, CXCL13 deficiency further improved the efficacy of a traditional chemotherapeutic drug (cyclophosphamide), as well as that of anti-programmed death receptor-1 immunotherapy. These results suggested that CXCL13 has an important role in regulating IL-10-producing B cells in tumor metastasis and might be a promising target for improving therapeutic efficiency and stimulating tumor immunity in future cancer therapy.

Dynamic Number and Function of IL-10-Producing Regulatory B Cells in the Immune Microenvironment at Distinct Stages of Type 1 Diabetes.

The critical role of IL-10-producing B cells (B10 cells) with a unique CD1dhiCD5+ phenotype in suppressing autoimmune responses and relieving inflammation has been demonstrated in several models of autoimmune diseases. However, the regulatory role of B10 cells in T cell-mediated autoimmune responses during the natural history of type 1 diabetes is unclear. In this study, we used the NOD mouse model of autoimmune diabetes to clarify the changes and potential mechanisms of B10 cells for disease. Compared with B10 cells present in the 4-wk-old normoglycemic NOD mice, the frequency of B10 cells was increased in the insulitis and diabetic NOD mice, with the highest proportion in the insulitis NOD mice. The changes in the relative number of B10 cells were most pronounced in the pancreas-draining lymph nodes. The pathogenic T cells, including Th1 and Th17 cells, remarkably increased. The assays in vitro showed that B10 cells in the NOD mice did not inhibit the proliferation of CD4+CD25- T cells. They also had no regulatory effect on IFN-γ and IL-4 secretion or on Foxp3 expression of T cells. B10 cells suppressed T cell-mediated autoimmune responses via an IL-10-dependent pathway. In contrast, B10 cells in the NOD mice exhibited a significant reduction in IL-10 production. In summary, a defect in the number and function of B10 cells may participate in the development and progression of type 1 diabetes.

Islet Lymphocytes Maintain a Stable Regulatory Phenotype Under Homeostatic Conditions and Metabolic Stress.

T cells and B cells have been identified in human and murine islets, but the phenotype and role of islet lymphocytes is unknown. Resident immune populations set the stage for responses to inflammation in the islets during homeostasis and diabetes. Thus, we sought to identify the phenotype and effector function of islet lymphocytes to better understand their role in normal islets and in islets under metabolic stress. Lymphocytes were located in the islet parenchyma, and were comprised of a mix of naïve, activated, and memory T cell and B cell subsets, with an enrichment for regulatory B cell subsets. Use of a Nur77 reporter indicated that CD8 T cells and B cells both received local antigen stimulus, indicating that they responded to antigens present in the islets. Analysis of effector function showed that islet T cells and B cells produced the regulatory cytokine IL-10. The regulatory phenotype of islet T cells and B cells and their response to local antigenic stimuli remained stable under conditions of metabolic stress in the diet induced obesity (DIO) model. T cells present in human islets retained a similar activated and memory phenotype in non-diabetic and T2D donors. Under steady-state conditions, islet T cells and B cells have a regulatory phenotype, and thus may play a protective role in maintaining tissue homeostasis.

Modulating Oxidative Stress in B Cells Promotes Immunotherapy in Food Allergy.

Allergen-specific immunotherapy (SIT) is the mainstay in the treatment of allergic diseases; its therapeutic efficacy is to be improved. Bacterial flagellin (FGN) has immune regulatory functions. This study investigates the role of FGN in promoting immunotherapy efficacy through modulating oxidative stress in regulatory B cells (Bregs). Blood samples were collected from patients with food allergy (FA) and healthy control (HC) subjects. CD19+ CD5+ Bregs were purified from blood samples by flow cytometry cell sorting. A murine FA model was developed with ovalbumin as the specific antigen. The results showed that peripheral Bregs from FA patients showed lower TLR5-related signals and higher apoptotic activities. The peripheral Breg frequency was negatively correlated with serum FGN levels in FA patients. Exposure to a specific antigen in culture induced antigen-specific Breg apoptosis that was counteracted by the presence of FGN. FGN diminished specific antigen-induced oxidative stress in Bregs. The STAT3/MAPKp38/NF-κB signal pathway was involved in the FGN/TLR5 signal-promoted superoxide dismutase expression in Bregs. Administration of FGN promotes the SIT efficacy in suppressing experimental FA. In summary, administration of FGN promotes SIT efficacy on FA, suggesting that the combination of FGN and SIT can be a novel therapy that has the translational potential to be employed in the treatment of allergic diseases.

Differences of Circulating CD25hi Bregs and Their Correlations with CD4 Effector and Regulatory T Cells in Autoantibody-Positive T1D Compared with Age-Matched Healthy Individuals.

Circulating CD25hi B cells, a subset of regulatory B cells in humans, are closely related to inflammation and autoimmune diseases. This study is aimed at investigating the alternation of CD25hi Bregs and their correlation with CD4 effector and regulatory T cells in T1D individuals. We included 68 autoantibody-positive T1D and 68 age-matched healthy individuals with peripheral blood mononuclear cells (PBMCs) and assessed them with CD25hi Bregs and CD4 effector or regulatory T cells by flow cytometry. Here, we demonstrate that the frequency of CD25hi Bregs was significantly decreased in T1D subjects (P = 0.0016), but they were not affected by disease status (age at T1D diagnosis or duration) or T1D risk loci (rs2104286 or rs12251307) in IL2RA (all P > 0.05). Moreover, higher IgD (P = 0.043) and lower CD27 (P = 0.0003) expression was observed in CD25hi Bregs of T1D individuals, but not the expression of IgM, CD24, or CD38 (all P > 0.05). Although there was no correlation between CD25hi Bregs and CD4 effector T cell subsets in either T1D or healthy individuals (all P > 0.05), we found a positive correlation between CD25hi Bregs and CD4 Tregs in healthy controls (Sp. r = 0.3544, P = 0.0249), which disappeared in T1D subjects (Sp. r = 0.137, P = 0.401). In conclusion, our results suggest that decreased CD25hi Bregs and alternation of their phenotypes are features of T1D regardless of disease duration and T1D genetic risk loci, and an impaired balance between CD25hi Bregs and CD4 Tregs might contribute to the pathogenesis of T1D.

Features of B Cell Responses Relevant to Allergic Disease.

This Brief Review delves into B cell responses in the context of allergy. The primary contribution of B cells to allergy is the production of IgE, the Ab isotype that triggers immediate hypersensitivity reactions through the release of mediators from mast cells and basophils. B cells may also have protective roles in allergy, such as through the production of IgG or as regulatory B cells. In this review, I focus on the basic principles of B cell differentiation and discuss features relevant to allergic immune responses. In particular, I discuss: (1) class-switch recombination; (2) plasma cell differentiation; (3) germinal centers and affinity maturation; and (4) memory B cells and recall responses, with an emphasis on IgE, IgG1, and IgG4. I also consider how B cells may contribute to allergic responses independent of Ab production-for example, by serving as APCs.

Chronic obstructive pulmonary disease is characterized by reduced levels and defective suppressive function of regulatory B cells in peripheral blood.

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive, persistent immune response to cigarette smoke, and it has been suggested that immune dysregulation is involved in its pathogenesis. A subset of regulatory B cells (Bregs) with high levels of the surface markers CD24 and CD38 (CD24hiCD38hi) has previously been shown to exert an immunosuppressive function. This study investigated the levels and activity of CD24hiCD38hi Bregs in stable COPD (sCOPD). Testing the peripheral blood from 65 patients with sCOPD and 39 control subjects for CD24hiCD38hi Breg subsets by flow cytometry showed that the patients with sCOPD had significantly lower levels of CD24hiCD38hi Bregs and IL-10+ B cells. The patients with sCOPD had lower serum interleukin-10 levels than the controls. The patients with most severe sCOPD had the lowest levels of CD24hiCD38hi Bregs. Spearman correlation analysis showed that the levels of CD24hiCD38hi Bregs in the patients with sCOPD positively correlated with serum interleukin-10 concentrations but not with levels of C-reactive protein. Compared to healthy controls, functional studies showed that Breg cells from patients with sCOPD exhibit a decreased suppressive function. We conclude that sCOPD is characterized by the exhaustion of CD24hiCD38hi regulatory B cells compartment. Therefore, CD24hiCD38hi Bregs may contribute to the pathogenesis of sCOPD.

B10 cells decrease fibrosis progression following cardiac injury partially by IL-10 production and regulating hyaluronan secretion.

B10 cells play negative roles in inflammatory disorders by producing IL-10. However, their effects on fibrosis have not been elucidated. Therefore, this study was conducted to examine the dynamic changes of B10 cell frequency and their potential role in cardiac fibrosis. We found that the frequency of B10 cells was significantly increased, and they participated in the regression of fibrosis via IL-10, particularly by accelerating hyaluronan secretion and inhibiting collagen deposition. In vivo, hyaluronan ablation or treatment significantly restricted cardiac fibrosis development. hyaluronan-induced conversion of M1/M2 Mc was dependent on the size of hyaluronan. Low molecular weight hyaluronan promoted the conversion to M1 Mϕ, whereas medium and high molecular weight hyaluronan accelerated Mϕ transdifferentiation into the M2 phenotype. Adoptive transfer of B10 cells significantly attenuated collagen deposition whereas CD19-/- mice with reduced B10 cells exacerbated fibrosis following cardiac injury. Our results provide new evidence suggesting that B10 cells exert antifibrotic effects by regulating the extracellular matrix composition during cardiac injury, and also highlight that B10 cells may serve as a promising therapeutic candidate for managing cardiac fibrosis-associated disorders.

Phenotypes, roles, and modulation of regulatory lymphocytes in periodontitis and its associated systemic diseases.

Periodontitis is a common chronic inflammatory disease that can result in tooth loss and poses a risk to systemic health. Lymphocytes play important roles in periodontitis through multiple mechanisms. Regulatory lymphocytes including regulatory B cells (Bregs) and T cells (Tregs) are the main immunosuppressive cells that maintain immune homeostasis, and are critical to our understanding of the pathogenesis of periodontitis and the development of effective treatments. In this review, we discuss the phenotypes, roles, and modulating strategies of regulatory lymphocytes including Bregs and Tregs in periodontitis and frequently cooccurring inflammatory diseases such as rheumatoid arthritis, Alzheimer disease, diabetes mellitus, and stroke. The current evidence suggests that restoring immune balance through therapeutic targeting of regulatory lymphocytes is a promising strategy for the treatment of periodontitis and other systemic inflammatory diseases.

Revolution of Disturbed Bregs and Bmems Lymphocytes Homeostasis in Children With Chronic ITP After High-dose Dexamethasone Rescue Therapy.

SUMMARY: Dexamethasone is approved as second-line therapy in pediatric chronic immune thrombocytopenic purpura (ITP). Several B-cell abnormalities have been described in ITP pathogenesis.This study assessed the effects of high-dose dexamethasone (HD-DXM) on the percentages and absolute counts of CD19+CD24hiCD38hi regulatory (Bregs) and CD19+CD27+ memory B lymphocytes (Bmems) in children with chronic ITP during active bleeding.The study was a prospective case-control, included 20 children with chronic ITP and uncontrolled bleeding. Children received a single daily dose of HD-DXM for 4 days. Blood samples were withdrawn from patients just before HD-DXM therapy and on day 5 to evaluate the platelet counts and flow cytometric analysis of Bregs and Bmem. The patients' platelet counts significantly increased after 5 days of the initiation of therapy (P=0.0001). Bmems percentage and absolute counts were significantly higher in patients before treatment (P=0.0007), and decreased after HD-DXM therapy (P=0.97) compared with the controls. Bregs percentage and absolute counts were significantly lower before treatment (P=0.0003) and increased after HD-DXM (P=0.003). There is a negative correlation between platelet counts and Bregs percentage and absolute count Bmems percentage before and after HD-DXM, whereas a positive correlation between platelets and Bregs before and after dexamethasone has been reported. CONCLUSIONS: HD-DXM reestablishes the normal Bregs/Bmems balance. This finding discloses possible involvement of Bregs and Bmems in the pathogenesis of pediatric ITP and provides a novel vision for immune modulation and treatment perspectives.

Short-Chain Fatty Acids Promote Immunotherapy by Modulating Immune Regulatory Property in B Cells.

The dysfunction of regulatory B cells (Breg) may result in immune inflammation such as allergic rhinitis (AR); the underlying mechanism is not fully understood yet. Short-chain fatty acids, such as propionic acid (PA), have immune regulatory functions. This study is aimed at testing a hypothesis that modulates PA production alleviating airway allergy through maintaining Breg functions. B cells were isolated from the blood obtained from AR patients and healthy control (HC) subjects. The stabilization of IL-10 mRNA in B cells was tested with RT-qPCR. An AR mouse model was developed to test the role of PA in stabilizing the IL-10 expression in B cells. We found that the serum PA levels were negatively correlated with the serum Th2 cytokine levels in AR patients. Serum PA levels were positively associated with peripheral CD5+ B cell frequency in AR patients; the CD5+ B cells were also IL-10+. The spontaneous IL-10 mRNA decay was observed in B cells, which was prevented by the presence of PA through activating GPR43. PA counteracted the effects of Tristetraprolin (TTP) on inducing IL-10 mRNA decay in B cells through the AKT/T-bet/granzyme B pathway. Administration of Yupinfeng San, a Chinese traditional medical formula, or indole-3-PA, induced PA production by intestinal bacteria to stabilize the IL-10 expression in B cells, which promoted the allergen specific immunotherapy, and efficiently alleviated experimental AR. In summary, the data show that CD5+ B cells produce IL-10. The serum lower PA levels are associated with the lower frequency of CD5+ B cells in AR patients. Administration with Yupinfeng San or indole-3-PA can improve Breg functions and alleviate experimental AR.

Crosstalk Between Circulating Follicular T Helper Cells and Regulatory B Cells in Children With Extrinsic Atopic Dermatitis.

Atopic dermatitis (AD) in early childhood is often the initial manifestation of allergic disease associated with high IgE. Accumulating evidences show that follicular helper T (Tfh) cells play a critical role in promoting B cell differentiation and IgE production, human regulatory B (Breg) cells participate in immunomodulatory processes and inhibition of allergic inflammation. However, the roles and interactions between IL-10-producing Breg cells and Tfh cells in childhood AD are unclear. In this study, we found that the percentage of CD19+IL-10+ Breg cells in children with extrinsic AD was significantly lower than that in age-matched healthy controls, and that it correlated negatively with enhanced CD4+CXCR5+PD-1+ICOS+ circulating Tfh cell responses and increased disease activity; however, there was no significant correlation with serum total IgE levels. A co-culture system revealed that Breg cells from patients with extrinsic AD cannot effectively inhibit differentiation of Tfh cells in an IL-10 dependent manner. Abnormal pSTAT3 signaling induced via Toll-like receptors (TLR), but not the B-cell receptor (BCR) signaling, might contribute to the defect of Breg cells in AD. Taken together, these observations demonstrate an important role for IL-10-producing Breg cells in inhibiting Tfh cell differentiation, and suggest that they may participate in the pathogenesis of AD.

IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice.

Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.

Indoleamine 2, 3-Dioxygenase Promotes Aryl Hydrocarbon Receptor-Dependent Differentiation Of Regulatory B Cells in Lung Cancer.

Regulatory B cells (Breg) are IL-10 producing subsets of B cells that contribute to immunosuppression in the tumor microenvironment (TME). Breg are elevated in patients with lung cancer; however, the mechanisms underlying Breg development and their function in lung cancer have not been adequately elucidated. Herein, we report a novel role for Indoleamine 2, 3- dioxygenase (IDO), a metabolic enzyme that degrades tryptophan (Trp) and the Trp metabolite L-kynurenine (L-Kyn) in the regulation of Breg differentiation in the lung TME. Using a syngeneic mouse model of lung cancer, we report that Breg frequencies significantly increased during tumor progression in the lung TME and secondary lymphoid organs, while Breg were reduced in tumor-bearing IDO deficient mice (IDO-/-). Trp metabolite L-Kyn promoted Breg differentiation in-vitro in an aryl hydrocarbon receptor (AhR), toll-like receptor-4-myeloid differentiation primary response 88, (TLR4-MyD88) dependent manner. Importantly, using mouse models with conditional deletion of IDO in myeloid-lineage cells, we identified a significant role for immunosuppressive myeloid-derived suppressor cell (MDSC)-associated IDO in modulating in-vivo and ex-vivo differentiation of Breg. Our studies thus identify Trp metabolism as a therapeutic target to modulate regulatory B cell function during lung cancer progression.

Interleukin-35 Prevents Development of Autoimmune Diabetes Possibly by Maintaining the Phenotype of Regulatory B Cells.

The anti-inflammatory role of regulatory B cells (Breg cells) has been associated with IL-35 based on studies of experimental autoimmune uveitis and encephalitis. The role of Breg cells and IL-35+ Breg cells for type 1 diabetes (T1D) remains to be investigated. We studied PBMCs from T1D subjects and healthy controls (HC) and found lowered proportions of Breg cells and IL-35+ Breg cells in T1D. To elucidate the role of Breg cells, the lymphoid organs of two mouse models of T1D were examined. Lower proportions of Breg cells and IL-35+ Breg cells were found in the animal models of T1D compared with control mice. In addition, the systemic administration of recombinant mouse IL-35 prevented hyperglycemia after multiple low dose streptozotocin (MLDSTZ) injections and increased the proportions of Breg cells and IL-35+ Breg cells. A higher proportion of IFN-γ+ cells among Breg cells were found in the PBMCs of the T1D subjects. In the MLDSTZ mice, IL-35 administration decreased the proportions of IFN-γ+ cells among the Breg cells. Our data illustrate that Breg cells may play an important role in the development of T1D and that IL-35 treatment prevents the development of hyperglycemia by maintaining the phenotype of the Breg cells under an experimental T1D condition.

IL-27-producing B-1a cells suppress neuroinflammation and CNS autoimmune diseases.

Regulatory B cells (Breg cells) that secrete IL-10 or IL-35 (i35-Breg) play key roles in regulating immunity in tumor microenvironment or during autoimmune and infectious diseases. Thus, loss of Breg function is implicated in development of autoimmune diseases while aberrant elevation of Breg prevents sterilizing immunity, exacerbates infectious diseases, and promotes cancer metastasis. Breg cells identified thus far are largely antigen-specific and derive mainly from B2-lymphocyte lineage. Here, we describe an innate-like IL-27-producing natural regulatory B-1a cell (i27-Breg) in peritoneal cavity and human umbilical cord blood. i27-Bregs accumulate in CNS and lymphoid tissues during neuroinflammation and confers protection against CNS autoimmune disease. i27-Breg immunotherapy ameliorated encephalomyelitis and uveitis through up-regulation of inhibitory receptors (Lag3, PD-1), suppression of Th17/Th1 responses, and propagating inhibitory signals that convert conventional B cells to regulatory lymphocytes that secrete IL-10 and/or IL-35 in eye, brain, or spinal cord. Furthermore, i27-Breg proliferates in vivo and sustains IL-27 secretion in CNS and lymphoid tissues, a therapeutic advantage over administering biologics (IL-10, IL-35) that are rapidly cleared in vivo. Mutant mice lacking irf4 in B cells exhibit exaggerated increase of i27-Bregs with few i35-Bregs, while mice with loss of irf8 in B cells have abundance of i35-Bregs but defective in generating i27-Bregs, identifying IRF8/BATF and IRF4/BATF axis in skewing B cell differentiation toward i27-Breg and i35-Breg developmental programs, respectively. Consistent with its developmental origin, disease suppression by innate i27-Bregs is neither antigen-specific nor disease-specific, suggesting that i27-Breg would be effective immunotherapy for a wide spectrum of autoimmune diseases.