B Cell-Derived IL-10 Does Not Regulate Spontaneous Systemic Autoimmunity in MRL.Faslpr Mice

Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519, USA.
The Journal of Immunology (Impact Factor: 4.92). 12/2011; 188(2):678-85. DOI: 10.4049/jimmunol.1102456
Source: PubMed


B cells contribute to the pathogenesis of chronic autoimmune disorders, like systemic lupus erythematosus (SLE), via multiple effector functions. However, B cells are also implicated in regulating SLE and other autoimmune syndromes via release of IL-10. B cells secreting IL-10 were termed "Bregs" and were proposed as a separate subset of cells, a concept that remains controversial. The balance between pro- and anti-inflammatory effects could determine the success of B cell-targeted therapies for autoimmune disorders; therefore, it is pivotal to understand the significance of B cell-secreted IL-10 in spontaneous autoimmunity. By lineage-specific deletion of Il10 from B cells, we demonstrated that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B and T cells during lupus. Correspondingly, severity of organ disease and survival rates in mice harboring Il10-deficient B cells are unaltered. Genetic marking of cells that transcribe Il10 illustrated that the pool of IL-10-competent cells is dominated by CD4 T cells and macrophages. IL-10-competent cells of the B lineage are rare in vivo and, among them, short-lived plasmablasts have the highest frequency, suggesting an activation-driven, rather than lineage-driven, phenotype. Putative Breg phenotypic subsets, such as CD1d(hi)CD5(+) and CD21(hi)CD23(hi) B cells, are not enriched in Il10 transcription. These genetic studies demonstrated that, in a spontaneous model of murine lupus, IL-10-dependent B cell regulation does not restrain disease and, thus, the pathogenic effects of B cells are not detectably counterbalanced by their IL-10-dependent regulatory functions.

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Available from: Mark Jay Shlomchik
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    • "While B cell-mediated immunosuppression by secretion of the anti-inflammatory cytokine interleukin-10 (IL-10) has received much recent attention, there are several reports of suppressive effects of B cells independent of IL-10, including in mouse models of type 1 diabetes and multiple sclerosis [5], [9]–[11]. Additionally, it was recently shown that selective deletion of IL-10 in B cells did not affect disease parameters in a mouse model of lupus, suggesting that the in vivo effects of endogenous regulation by IL-10-producing B cells may be more subtle than previously thought [12]. Therefore, understanding the full repertoire of immunosuppressive mechanisms employed by B cells is crucial for appreciating their role in maintaining self-tolerance [13]. "
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    ABSTRACT: Beyond their critical role in humoral immunity, B lymphocytes can employ a variety of immunomodulatory mechanisms including expression of the apoptosis-inducing molecule Fas ligand (FasL; CD178). Here, we extensively characterized the surface phenotype of FasL(+) killer B cells, showing they are enriched in the IgM(high)CD5(+)CD1d(high) B cell subset previously reported to contain a higher frequency of B cells producing interleukin-10 (IL-10). A rare population of B cells expressing IL-10 was present among FasL(+) B cells, but most FasL(+) B cells did not produce IL-10. We also identify interleukin-5 (IL-5) as a novel inducer of killer B cell function. Constitutively FasL(+) B cells expressed higher levels of the IL-5 receptor, and treating B cells with IL-5 and CD40L resulted in the expansion of a B cell population enriched for FasL(+) cells. B cells stimulated with IL-5 and CD40L were potent inducers of apoptosis in activated primary CD4(+) T cells, and this killing function was antigen-specific and dependent upon FasL. IL-5 also enhanced IL-10 secretion in B cells stimulated with CD40L. Taken together these findings elucidate the relationship of FasL(+) B cells and IL-10-producing B cells and demonstrate that IL-5 can induce or enhance both killer B cell activity and IL-10 secretion in B cells. Finally, we found that the killer B cell activity induced by IL-5 was completely blocked by IL-4, suggesting the existence of a previously unknown antagonistic relationship between these type-2 cytokines in modulating the activity of killer B cells. Targeting this IL-5/IL-4 signaling axis may therefore represent a novel area of drug discovery in inflammatory disorders.
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    • "In this study, however, only the IL-10 secreted by endogenous B10 cells was absent. IL-10 is typically produced by other B-cell subsets as well [47], and the progenitor B10 cells, which are a main source of IL-10 [17], [51], were not deleted in this study. Thus, insufficient data is available to solidly conclude that B10 cells do not limit disease in MRL/lpr mice [47]. "
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    ABSTRACT: T follicular helper (Tfh) cells can mediate humoral immune responses and augment autoimmunity, whereas the role of Tfh cells on regulatory B (B10) cells in autoimmunity diseases is not clear. Here, we investigated the percentages of Tfh cells and B10 cells in lupus-prone MRL/Mp-lpr/lpr (MRL/lpr) mice and examined the effects and mechanism of Tfh cell-derived interleukin-21 (IL-21) on IL-10 production during the differentiation of B10 cells. Both Tfh cells and B10 cells were expanded in spleens of MRL/lpr mice. In addition, a positive correlation between the proportions of Tfh cells and B10 cells was observed. Tfh cell-derived IL-21 from MRL/lpr mice could promote IL-10 production during the differentiation of B10 cells. Importantly, neutralization of IL-21 inhibited IL-10 production and expansion of B10 cells both in vitro and in vivo. IL-21 induced IL-10 production via activation of phosphorylated signal transduction and activator of transcription 3 (p-STAT3). Inhibition of p-STAT3 effectively blocked IL-10 production during the differentiation of B10 cells. Moreover, IL-21-induced IL-10 exerted a regulatory function by inhibiting the proliferation of T cells. These data suggest that Tfh cells not only mediate humoral immune responses and augment autoimmunity but also play a broader role in immune regulatory actions via the induction of IL-10 production.
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    • "In the MRL.Fas(lpr) mouse lupus model, B cell-derived IL-10 does not regulate spontaneous autoimmunity [89]. B cell-specific deletion of IL-10 in MRL.Fas(lpr) mice indicates that B cell-derived IL-10 is ineffective in suppressing the spontaneous activation of self-reactive B cells and T cells during lupus. "
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