SUMMARY B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has so far been associated primarily with interleukin (IL)-10 because B cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens1,2. Here, we identify IL-35-producing B cells as novel key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a strikingly improved resistance to infection with the intracellular bacterial pathogen Salmonella typhimurium, as shown by their superior containment of the bacterial growth and their prolonged survival both after primary infection, and upon secondary challenge after vaccination, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an enhanced stimulatory function of B cells as antigen-presenting cells (APC). During Salmonella infection IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM+CD138hiTACI+CXCR4+CD1dintTim1int plasma cells expressing the transcription factor Blimp1. During EAE CD138+ plasma cells were also the major source of B cell-derived IL-35 and IL-10. Collectively, our data unravel the importance of IL-35-producing B cells in regulation of immunity, and highlight IL-35 production by B cells as a novel therapeutic target for autoimmune and infectious diseases. More generally, this study emphasizes the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.

SummaryB lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention.

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B cells and regulatory T (Treg) cells can both facilitate remission from experimental auto immune encephalomyelitis (EAE), a disease of the central nervous system (CNS) used as a model for multiple sclerosis (MS). Considering that B-cell-depletion therapy (BCDT) is used to treat MS patients, we asked whether Treg-cell activation depended on B cells during EAE. Treg-cell proliferation, accumulation in CNS, and augmentation of suppressive activity in the CNS were normal in B-cell-deficient mice, indicating that B cells are not essential for activation of the protective Treg-cell response and thus provide an independent layer of regulation. This function of B cells involved early suppression of the encephalitogenic CD4+ T-cell response, which was enhanced in B-cell-deficient mice. CD4+ T-cell depletion was sufficient to intercept the transition from acute-to-chronic EAE when applied to B-cell-deficient animals that just reached the peak of disease severity. Intriguingly, this treatment did not improve disease when applied later, implying that chronic disability was ultimately maintained independently of pathogenic CD4 + T cells. Collectively, our data indicate that BCDT is unlikely to impair Treg-cell function, yet it might produce undesirable effects on T-cell-mediated autoimmune pathogenesis.Keywords: Autoimmunity r B cells r EAE r MS r Regulatory T cells IntroductionExperimental autoimmune encephalomyelitis (EAE) is a T-cellmediated inflammatory disease associated with the development of demyelinating lesions in central nervous system (CNS). It is widely used as an animal model for relapsing-remitting multiple sclerosis (RR-MS) [1]. EAE can be induced in genetically susceptible animals by immunization with myelin antigens such as myelin oligodendrocyte glycoprotein (MOG). After onset of paralysis, animals can spontaneously recover from disease, providing a modelCorrespondence: Dr. Simon Fillatreau e-mail: fillatreau@drfz.de to investigate how remission from disease flares might be regulated during RR-MS. Remission from EAE involves IL-10-producing B cells and CD4 + Foxp3 + regulatory T (Treg) cells [2,3]. These two protective cell types might be impaired in RR-MS because Treg cells from RR-MS patients were less suppressive, and B cells produced less IL-10, than the corresponding cells from healthy individuals [4,5]. Furthermore, standard treatments for RR-MS (IFN-β and glatiramer acetate) can enhance the suppressive functions of Treg cells or B cells [5][6][7]. It might also be relevant that helminth parasites can increase the regulatory functions of Treg and B cells, and reduce rate of relapses in RR-MS patients [8,9]. + CD8 − T cells in thymus, and (H, I) among CD4 + T cells in (H) spleen, and (I) LNs of naïve adult C57BL/6 (black bars) and JHT (white bars) mice. Data are representative of (B, F) or show mean + SEM (C-E, G-I) of data pooled from at least three independent experiments (four mice per group per experiment). ***p < 0.0001, unpaired t-test.early involvement of B cells and a later action of Treg cel...

B cells are usually considered primarily for their unique capacity to produce antibodies after differentiation into plasma cells. In addition to their roles as antibody-producing cells, it has become apparent during the last 10 years that B cells also perform important functions in immunity through the production of cytokines. In particular, it was shown that B cells could negatively regulate immunity through provision of interleukin (IL)-10 during autoimmune and infectious diseases in mice. Here, we review data on the suppressive functions of B cells in mice with particular emphasis on the signals controlling the acquisition of such suppressive functions by B cells, the phenotype of the B cells involved in the negative regulation of immunity, and the processes targeted by this inhibitory circuit. Finally, we discuss the possibility that human B cells might also perform similar inhibitory functions through the provision of IL-10, and review data suggesting that such B cell-mediated regulatory activities might be impaired in patients with autoimmune diseases.

Here, we review current knowledge on the B-cell subpopulations found to provide suppressive functions in mice, considering both the pathological context in which they were identified and the signals that control their induction. We discuss the phenotype of B cells that have IL-10-dependent regulatory activities in mice, which leads us to propose that antibody-secreting cells are, in some cases at least, the major source of B-cell-derived regulatory IL-10 in vivo. Anti-inflammatory cytokine production by antibody-secreting cells offers a novel mechanism for the coordination of innate and humoral immune responses.

Cerebral malaria is a life-threatening complication of malaria in humans, and the underlying pathogenic mechanisms are widely analyzed in a murine model of experimental cerebral malaria (ECM). Here, we show abrogation of ECM by hemocoel sporozoite-induced infection of a transgenic Plasmodium berghei line that overexpresses profilin, whereas these parasites remain fully virulent in transfusion-mediated blood infection. We, thus, demonstrate the importance of the clinically silent liver-stage infection for modulating the onset of ECM. Even though both parasites triggered comparable splenic immune cell expansion and accumulation of antigen-experienced CD8+ T cells in the brain, infection with transgenic sporozoites did not lead to cerebral vascular damages and suppressed the recruitment of overall lymphocyte populations. Strikingly, infection with the transgenic strain led to maintenance of CD115+Ly6C+ monocytes, which disappear in infected animals prone to ECM. An early induction of IL-10, IL-12p70, IL-6, and TNF at the time when parasites emerge from the liver might lead to a diminished induction of hepatic immunity. Collectively, our study reveals the essential role of early host interactions in the liver that may dampen the subsequent pro-inflammatory immune responses and influence the occurrence of ECM, highlighting a novel checkpoint in this fatal pathology.

Rheumatoid arthritis (RA) is associated with abnormal B cell-functions implicatingantibody-dependent and -independent mechanisms. B cells have emerged as important cytokine-producing cells, and cytokines are well-known drivers of RA pathogenesis. To identify novel cytokine-mediated B-cell functions in RA, we comprehensively analysed the capacity of B cells from RA patients with an inadequate response to disease modifying anti-rheumatic drugs to produce cytokines in comparison with healthy donors (HD). RA B cells displayed a constitutively higher production of the pathogenic factors interleukin (IL)-8 and Gro-α, while their production of several cytokines upon activation via the B cell receptor for antigen (BCR) was broadly suppressed, including a loss of the expression of the protective factor TRAIL, compared to HD B cells. These defects were partly erased after treatment with the IL-6-signalling inhibitor tocilizumab, indicating that abnormal IL-6 signalling contributed to these abnormalities. Noteworthy, the clinical response of individual patients to tocilizumab therapy could be predicted using the amounts of MIP-1β and β-NGF produced by these patients' B cells before treatment. Taken together, our study highlights hitherto unknown abnormal B-cell functions in RA patients, which are related to the unbalanced cytokine network, and are potentially relevant for RA pathogenesis and treatment.