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B cells critically contribute to health through the production of antibodies that provide a vital line of defence against infectious agents. In addition, B cells are known to play an integrative role in immunity, acting as crucial antigen-presenting cells for T cells, and being an important source of cytokines that can target multiple cell types including stromal cells, innate cells, and adaptive lymphocytes. This review focuses on the role of B cells as negative regulators of immunity through the production of interleukin-10 (IL-10) in autoimmune, infectious, and malignant diseases. It discusses the phenotypes of the B cell subsets most competent to produce IL-10 in vitro and to exert suppressive functions in vivo upon adoptive transfer in recipient mice, the signals and transcription factors regulating IL-10 expression in B cells, and the recent identification of plasmocytes, including short-lived plasmablasts and long-lived plasma cells, as an important source of IL-10 in secondary lymphoid organs and inflamed tissues in vivo during mouse and human diseases. With our increasing knowledge of this non-canonical B cell function a coherent framework starts emerging that will help monitoring and targeting this B cell function in health and disease.

The cellular components of the plasma cell niche in the bone marrow have remained elusive. Berek and co-workers show that eosinophils are key providers of plasma cell survival factors in the bone marrow. Plasma cells are of crucial importance for long-term immune protection. It is thought that long-lived plasma cells survive in specialized niches in the bone marrow. Here we demonstrate that bone marrow eosinophils localized together with plasma cells and were the key providers of plasma cell survival factors. In vitro , eosinophils supported the survival of plasma cells by secreting the proliferation-inducing ligand APRIL and interleukin-6 (IL-6). In eosinophil-deficient mice, plasma cell numbers were much lower in the bone marrow both at steady state and after immunization. Reconstitution experiments showed that eosinophils were crucial for the retention of plasma cells in the bone marrow. Moreover, depletion of eosinophils induced apoptosis in long-lived bone marrow plasma cells. Our findings demonstrate that the long-term maintenance of plasma cells in the bone marrow requires eosinophils.

Hypoxia-inducible factors (HIFs) are key elements for controlling immune cell metabolism and functions. While HIFs are known to be involved in T cells and macrophages activation, their functions in B lymphocytes are poorly defined. Here, we show that hypoxia-inducible factor-1α (HIF-1α) contributes to IL-10 production by B cells. HIF-1α regulates IL-10 expression, and HIF-1α-dependent glycolysis facilitates CD1d hi CD5 + B cells expansion. Mice with B cell-specific deletion of Hif1a have reduced number of IL-10-producing B cells, which result in exacerbated collagen-induced arthritis and experimental autoimmune encephalomyelitis. Wild-type CD1d hi CD5 + B cells, but not Hif1a -deficient CD1d hi CD5 + B cells, protect recipient mice from autoimmune disease, while the protective function of Hif1a -deficient CD1d hi CD5 + B cells is restored when their defective IL-10 expression is genetically corrected. Taken together, this study demonstrates the key function of the hypoxia-associated transcription factor HIF-1α in driving IL-10 expression in CD1d hi CD5 + B cells, and in controlling their protective activity in autoimmune disease. B cells are important for antigen presentation and antibody production in humoral immunity, but are also increasingly recognized for their immune regulatory functions. Here the authors show that HIF-1α, a hypoxia-induced transcription factor, is important for controlling IL-10 induction in and immune-suppressive activity of B cells.

Key Points Through the production of cytokines, B cells influence multiple aspects of immunity. B cell-derived cytokines guide the development of lymphoid tissues, shape and promote effector and memory T cell responses and can also negatively regulate immune responses. The roles of B cells in lymphoid organogenesis often depends on their production of lymphotoxin α1β2 (LTα1β2). B cells can drive tertiary lymphoid tissue formation independently of lymphoid tissue-inducer cells by producing LTα1β2. Following tissue damage, B cells can produce cytokines that influence tissue regeneration and pathophysiology in non-immunological organs. B cells can control the polarization of effector T cell responses and the formation of memory T cells through the provision of cytokines. B cells can negatively regulate immune response by producing interleukin-10 (IL-10) and IL-35. Subsets of CD19 + CD138 hi 'regulatory plasma cells' are the major sources of these B cell-derived suppressive cytokines in vivo . B cells from mice infected with helminth parasites can inhibit allergic inflammation through the production of IL-10. Although they are better known for their roles in antibody responses, B cells also contribute to immunity by secreting cytokines. Here, the authors discuss the various ways in which B cells can shape the immune response during infection and inflammatory disease by producing both pro-inflammatory and immunosuppressive cytokines. Cytokine production by B cells is important for multiple aspects of immunity. B cell-derived cytokines, including lymphotoxin, are essential for the ontogenesis, homeostasis and activation of secondary lymphoid organs, as well as for the development of tertiary lymphoid tissues at ectopic sites. Other B cell-derived cytokines, such as interleukin-6 (IL-6), interferon-γ and tumour necrosis factor, influence the development of effector and memory CD4 + T cell responses. Finally, B cells can regulate inflammatory immune responses, primarily through their provision of IL-10 and IL-35. This Review summarizes these various roles of cytokine-producing B cells in immunity and discusses the rational for targeting these cells in the clinic.

Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at an early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that were required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP 1–39 at the peak of EAE promoted disease remission. In vitro, CRAMP 1–39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR) 2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors 2/3 (FFAR2/3), and prevented EAE. This study shows that CRAMP produced by different cell types has opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.

CD4 Foxp3 T regulatory cells (Treg) are essential for the life of the organism, in particular because they protect the host against its own autoaggressive CD4 Foxp3 T lymphocytes (Tconv). Treg distinctively suppress autoaggressive immunity while permitting efficient defense against infectious diseases. This split effect indicates that Treg activity is controlled in an antigen-specific manner. This specificity is achieved first by the formation of the Treg repertoire during their development, and second by their activation in the periphery. This review presents novel information on the antigen-specificity of Treg development in the thymus, and Treg function in the periphery. These aspects have so far remained imprecisely understood due to the lack of knowledge of the actual antigens recognized by Treg during the different steps of their life, so that most previous studies have been performed using artificial antigens. However, recent studies identified some antigens mediating the positive selection of autoreactive Treg in the thymus, and the function of Treg in the periphery in autoimmune and allergic disorders. These investigations emphasized the remarkable specificity of Treg development and function. Indeed, the development of autoreactive Treg in the thymus was found to be mediated by single autoantigens, so that the absence of one antigen led to a dramatic loss of Treg reacting toward that antigen. The specificity of Treg development is important because the constitution of the Treg repertoire, and especially the presence of holes in this repertoire, was found to crucially influence human immunopathology. Indeed, it was found that the development of human immunopathology was permitted by the lack of Treg against the antigens driving the autoimmune or allergic T cell responses rather than by the impairment of Treg activation or function. The specificity of Treg suppression in the periphery is therefore intimately associated with the mechanisms shaping the formation of the Treg repertoire during their development. This novel information refines significantly our understanding of the antigen-specificity of Treg protective function, which is required to envision how these cells distinctively regulate unwanted immune responses as well as for the development of appropriate approaches to optimally harness them therapeutically in autoimmune, malignant, and infectious diseases.

Adjuvants play an essential role in the induction of acquired immunity upon vaccination with protein antigen. In this issue of EMBO Molecular Medicine , a classical type of adjuvant made of DNA oligonucleotide containing CpG motifs, which has already been used in humans, is shown to boost humoral immunity primarily by acting on monocyte‐derived dendritic cells. This study provides novel insight on the mode of action of adjuvant targeting Toll‐like receptors. Graphical Abstract In this issue of EMBO Molecular Medicine, an adjuvant containing CpG motifs and thereby targeting Toll‐like receptors is shown to boost humoral immunity by primarily acting on monocyte‐derived dendritic cells.

Upon infection, B-lymphocytes expressing antibodies specific for the intruding pathogen develop clonal responses triggered by pathogen recognition via the B-cell receptor. The constant region of antibodies produced by such responding clones dictates their functional properties. In teleost fish, the clonal structure of B-cell responses and the respective contribution of the three isotypes IgM, IgD and IgT remain unknown. The expression of IgM and IgT are mutually exclusive, leading to the existence of two B-cell subsets expressing either both IgM and IgD or only IgT. Here, we undertook a comprehensive analysis of the variable heavy chain (VH) domain repertoires of the IgM, IgD and IgT in spleen of homozygous isogenic rainbow trout (Onchorhynchus mykiss) before, and after challenge with a rhabdovirus, the Viral Hemorrhagic Septicemia Virus (VHSV), using CDR3-length spectratyping and pyrosequencing of immunoglobulin (Ig) transcripts. In healthy fish, we observed distinct repertoires for IgM, IgD and IgT, respectively, with a few amplified μ and τ junctions, suggesting the presence of IgM- and IgT-secreting cells in the spleen. In infected animals, we detected complex and highly diverse IgM responses involving all VH subgroups, and dominated by a few large public and private clones. A lower number of robust clonal responses involving only a few VH were detected for the mucosal IgT, indicating that both IgM(+) and IgT(+) spleen B cells responded to systemic infection but at different degrees. In contrast, the IgD response to the infection was faint. Although fish IgD and IgT present different structural features and evolutionary origin compared to mammalian IgD and IgA, respectively, their implication in the B-cell response evokes these mouse and human counterparts. Thus, it appears that the general properties of antibody responses were already in place in common ancestors of fish and mammals, and were globally conserved during evolution with possible functional convergences.

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 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.

The enzyme fructose-bisphosphate aldolase occupies a central position in glycolysis and gluconeogenesis pathways. Beyond its housekeeping role in metabolism, fructose-bisphosphate aldolase has been involved in additional functions and is considered as a potential target for drug development against pathogenic bacteria. Here, we address the role of fructose-bisphosphate aldolase in the bacterial pathogen Francisella novicida. We demonstrate that fructose-bisphosphate aldolase is important for bacterial multiplication in macrophages in the presence of gluconeogenic substrates. In addition, we unravel a direct role of this metabolic enzyme in transcription regulation of genes katG and rpoA, encoding catalase and an RNA polymerase subunit, respectively. We propose a model in which fructose-bisphosphate aldolase participates in the control of host redox homeostasis and the inflammatory immune response.