TLR sense microbial infections, and control activation of immune responses. Dendritic cells, macrophages, and B lymphocytes express TLR and the TLR-signaling adaptor protein MyD88. The impact of TLR-activated B cells on T cell-mediated inflammation is unknown. In this study, we have used mice carrying B cell-restricted deficiencies in MyD88 or in distinct TLR to examine the impact of TLR-activated B cells on a T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). We demonstrate that TLR-signaling in B cells suppresses inflammatory T cell responses (both Th1 and Th17), and stimulates recovery from EAE. Only certain TLR are required on B cells for resolution of EAE, and these are dispensable for disease initiation, indicating that a category of TLR agonists preferentially triggers a suppressive function in B cells and thereby limits autoimmune disease. The TLR agonists controlling the regulatory function of B cells are provided by components of Mycobacterium tuberculosis present in the adjuvant. Thus, MyD88 signaling in B cells antagonizes MyD88 signaling in other cells, which drives differentiation of Th17 cells and is required for induction of EAE. Altogether, our data indicate that B cells link recognition of microbial products via TLR to suppression of a T cell-mediated autoimmune disease.
The myeloid differentiation primary response gene 88 (Myd88) is critical for protection against pathogens. However, we demonstrate here that MyD88 expression in B cells inhibits resistance of mice to Salmonella typhimurium infection. Selective deficiency of Myd88 in B cells improved control of bacterial replication and prolonged survival of the infected mice. The B cell-mediated suppressive pathway was even more striking after secondary challenge. Upon vaccination, mice lacking Myd88 in B cells became completely resistant against this otherwise lethal infection, whereas control mice were only partially protected. Analysis of immune defenses revealed that MyD88 signaling in B cells suppressed three crucial arms of protective immunity: neutrophils, natural killer cells, and inflammatory T cells. We further show that interleukin-10 is an essential mediator of these inhibitory functions of B cells. Collectively, our data identify a role for MyD88 and B cells in regulation of cellular mechanisms of protective immunity during infection.
B lymphocytes contribute to immunity through production of antibodies, antigen presentation to T cells, and secretion of cytokines. B cells are generally considered in autoimmune diseases as drivers of pathogenesis. This view is certainly justified, given the successful utilization of the B cell-depleting reagent rituximab in patients with rheumatoid arthritis or other autoimmune pathologies. In a number of cases, however, the depletion of B cells led to an exacerbation of symptoms in patients with autoimmune disorders. In a similar manner, mice lacking B cells can develop an aggravated course of disease in several autoimmune models. These paradoxical observations are now explained by the concept that activated B cells can suppress immune responses through the production of cytokines, especially interleukin-10. Here, we review the stimulatory signals that induce interleukin-10 secretion and suppressive functions in B cells and the phenotype of the B cells with such characteristics. Finally, we formulate a model explaining how this process of immune regulation by activated B cells can confer advantageous properties to the immune system in its combat with pathogens. Altogether, this review proposes that B-cell-mediated regulation is a fundamental property of the immune system, with features of great interest for the development of new cell-based therapies for autoimmune diseases.
Here we describe a novel vaccine vector for expressing human immunodeficiency virus (HIV) antigens. We show that recombinant attenuated yellow fever vaccine virus 17D expressing simian immunodeficiency virus SIVmac239 Gag sequences can be used as a vector to generate SIV-specific CD8؉ T-cell responses in the rhesus macaque. Priming with recombinant BCG expressing SIV antigens increased the frequency of these SIVspecific CD8؉ T-cell responses after recombinant YF17D boosting. These recombinant YF17D-induced SIVspecific CD8؉ T cells secreted several cytokines, were largely effector memory T cells, and suppressed viral replication in CD4 ؉ T cells.
Activated B cells can regulate immunity, and have been envisaged as potential cell-based therapy for treating autoimmune diseases. However, activated human B cells can also propagate immune responses, and the effects resulting from their infusion into patients cannot be predicted. This led us to consider resting B cells, which in contrast are poorly immunogenic, as an alternative cellular platform for the suppression of unwanted immunity. Here, we report that resting B cells can be directly engineered to express antigens in a remarkably simple, rapid, and effective way with lentiviral vectors. Notably, this neither required nor induced activation of the B cells. With that approach we were able to produce reprogrammed resting B cells that inhibited antigen-specific CD4+ T cells, CD8+ T cells, and B cells upon adoptive transfer in mice. Furthermore, resting B cells engineered to ectopically express myelin oligodendrocyte glycoprotein antigen protected recipient mice from severe disability and demyelination in experimental autoimmune encephalomyelitis, and even induced complete remission from disease in mice lacking functional natural regulatory T cells, which otherwise developed a chronic paralysis. In conclusion, our study introduces reprogrammed quiescent B cells as a novel tool for suppressing undesirable immunity.
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