RESUMEN
The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27- and memory IgD-CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans.
Asunto(s)
Linfocitos B , Proteínas Proto-Oncogénicas c-akt , Humanos , Ratones , Animales , Tejido Linfoide , Transducción de Señal , BazoRESUMEN
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.
Asunto(s)
Hepatopatías/parasitología , Hígado/parasitología , Malaria Cerebral/parasitología , Plasmodium berghei/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Citocinas/sangre , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Parásitos , Hepatopatías/sangre , Hepatopatías/inmunología , Malaria Cerebral/sangre , Malaria Cerebral/inmunología , Ratones Endogámicos C57BL , Monocitos/inmunología , Bazo/citologíaRESUMEN
B 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.
Asunto(s)
Antígenos CD/genética , Expresión Génica , Interleucina-10/biosíntesis , Células Plasmáticas/inmunología , Animales , Antígenos CD/inmunología , Subgrupos de Linfocitos B/inmunología , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Interleucina-10/genética , Activación de Linfocitos , Masculino , Ratones , Células Plasmáticas/fisiología , Receptores de Antígenos de Linfocitos B/metabolismo , Salmonelosis Animal/inmunología , Transducción de Señal , Linfocitos T/inmunología , Receptores Toll-Like/metabolismo , Regulación hacia Arriba/genética , Vacunas/inmunología , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Rheumatoid arthritis (RA) is associated with abnormal B cell-functions implicating antibody-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-1ß and ß-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.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Linfocitos B/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Artritis Reumatoide/inmunología , Quimiocina CCL4/biosíntesis , Quimiocina CXCL1/biosíntesis , Humanos , Interleucina-8/biosíntesis , Factor de Crecimiento Nervioso/biosíntesis , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesisRESUMEN
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.
Asunto(s)
Linfocitos B/inmunología , Interleucina-10/fisiología , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Listeriosis/inmunología , Infecciones por Salmonella/inmunología , Salmonella typhimuriumRESUMEN
B lymphocytes have a unique role as antibody-producing cells. Antibodies are key mediators of humoral immunity against infections, and are thought to account for the protection afforded by successful vaccines. B cells can also secrete cytokines and subsequently regulate immune responses mediated by T and innate cells. Remarkably, recent studies identified plasma blasts/plasma cells as the main types of activated B cells producing the cytokines interleukin (IL)-10, IL-35, tumor necrosis factor (TNF)-α, IL-17, and GM-CSF in various contexts in mice. Here, we discuss these observations, which suggest the existence of various subsets of plasma blast/plasma cells distinguishable through their cytokine expression pattern.
Asunto(s)
Linfocitos B/inmunología , Diferenciación Celular , Citocinas/inmunología , Células Plasmáticas/inmunología , Animales , Linfocitos B/citología , Citocinas/biosíntesis , Humanos , Óxido Nítrico Sintasa de Tipo II/inmunología , Células Plasmáticas/citología , Trypanosoma cruzi/inmunologíaRESUMEN
B-cell depletion can improve disease in some patients with rheumatoid arthritis or multiple sclerosis, indicating the pathogenic contribution of B cells to autoimmunity. However, studies in mice have demonstrated that B cells have immunosuppressive functions as well, with IL-10 being a critical mediator of B-cell-mediated suppression. IL-10-secreting B cells have been shown to promote disease remission in some mouse models of autoimmune disorders. Human B cells also produce IL-10, and evidence is accumulating that human IL-10-producing B cells might inhibit immunity. There is considerable interest in identifying the phenotype of B cells providing IL-10 in a suppressive manner, which would facilitate the analysis of the molecular mechanisms controlling this B-cell property. 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.
Asunto(s)
Artritis Reumatoide/inmunología , Linfocitos B Reguladores/inmunología , Interleucina-10/metabolismo , Esclerosis Múltiple/inmunología , Células Plasmáticas/inmunología , Animales , Artritis Reumatoide/patología , Linfocitos B Reguladores/patología , Humanos , Inmunidad Humoral , Inmunidad Innata , Ratones , Esclerosis Múltiple/patología , Células Plasmáticas/patologíaRESUMEN
B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as 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 markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, 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 increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals 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.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Encefalomielitis Autoinmune Experimental/inmunología , Inmunidad/inmunología , Interleucinas/metabolismo , Infecciones por Salmonella/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos CD40/inmunología , Femenino , Humanos , Interleucina-10/metabolismo , Interleucinas/inmunología , Activación de Linfocitos , Macrófagos/citología , Macrófagos/inmunología , Masculino , Ratones , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Infecciones por Salmonella/microbiología , Linfocitos T/inmunología , Receptor Toll-Like 4/inmunologíaRESUMEN
B cells can contribute to immunity through production of antibodies, presentation of antigen to T cells, and secretion of cytokines. B cell activation can result in various outcomes for the host. In general B cell responses are beneficial during infections, and deleterious during autoimmune diseases. However, B cells can also limit host defence against pathogens, and protect from autoimmune pathologies. B cells can therefore act both as drivers and as regulators of immunity. Understanding how these opposite functions are mediated shall stimulate the elaboration of novel approaches for manipulating the immune system. B cells might acquire distinct functional properties depending on their mode of activation. Antigen-specific B cell responses require triggering of B cell receptor (BCR) by antigen, and provision of helper signals by T cells. B cells also express various innate immune receptors, and can directly respond to microbial products. Here, we discuss how intrinsic signalling via Toll-like receptors contributes to the suppressive functions of B cells during autoimmune and infectious diseases.
Asunto(s)
Linfocitos B/metabolismo , Enfermedades Transmisibles/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Transducción de Señal/inmunología , Receptores Toll-Like/metabolismo , Linfocitos B/inmunología , Humanos , Receptores Toll-Like/inmunologíaRESUMEN
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.
Asunto(s)
Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Factores de Transcripción Forkhead/inmunología , Linfocitos T Reguladores/inmunología , Enfermedad Aguda , Traslado Adoptivo , Animales , Enfermedad Crónica , Activación de Linfocitos/inmunología , Depleción Linfocítica , Ratones , Índice de Severidad de la EnfermedadRESUMEN
The immune system is composed of multiple cell types, which together improve the resistance of the organism against infections. The unfolding of a successful host response ensuring effective protection against pathogens requires an appropriate coordination of the different players of the immune system. Innate cells and T cells extensively communicate during immune reactions, providing multiple opportunities for the mutual coordination of these two defense pathways. Little is known about the functional interactions between B and innate cells, and it is generally assumed that they influence each other indirectly through effects on T cells. However, recent studies highlighted important roles for innate cells in initial presentation of antigen to B cells after immunization, and in long-term maintenance of antibody-producing cells in bone marrow after resolution of immune responses. Furthermore, it was found that activated B cells could regulate the activity of innate cells through production of cytokines. Here, we review how direct interactions between innate and B cells can contribute to orchestration of humoral and cellular immunity.