A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells

Hua, C.; Audo, Rachel; Yeremenko, Nataliya; Baeten, Dominique; Hahne, Michael; Combe, Bernard; Morel, Jacques; Daïen, C.

doi:10.1016/j.jaut.2016.06.002

Cited by 60 publications

(66 citation statements)

References 23 publications

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“…In monocytes and macrophages, the MAPKs c‐Jun N‐terminal kinases (JNK), p38 and ERK1/2 are involved in TLR‐induced IL‐10 production and are tightly controlled by IFN‐γ . In B cells, it has been demonstrated that p38, JNK and ERK1/2 are important for IL‐10 production . We confirmed the importance of these MAPKs in IL‐10 production by B cells.…”

Section: Resultssupporting

confidence: 74%

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IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

et al. 2018

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The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production.

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Section: Resultssupporting

confidence: 74%

“…In fact, the authors showed that another member of the same family, i.e. a proliferation‐inducing ligand (APRIL) did increase IL‐10 production by CpG‐stimulated B cells . In our study, we did not specifically investigate the role of APRIL.…”

Section: Discussionmentioning

confidence: 85%

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

et al. 2018

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“…We also found IL-10 was produced at significantly higher levels by TACI hi than TACI low splenic B-lymphocytes from untreated NOD mice (Supplemental Figure 3A). The TACI hi B-lymphocytes can in theory rely on APRIL for their survival upon BAFF-starvation, and activation of this alternative survival axis might promote IL-10 production (43). …”

Section: Resultsmentioning

confidence: 99%

Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy

Wang

Racine

Ratiu

et al. 2017

The Journal of Immunology

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In NOD mice and also likely humans, B-lymphocytes play an important role as APC expanding autoreactive T-cell responses ultimately causing type 1 diabetes (T1D). Currently, humans at high future T1D risk can only be identified at late prodromal stages of disease indicated by markers such as insulin autoantibodies (IAA). When commenced in already IAA+ NOD mice, continuous BAFFR-Fc treatment alone or in combination with anti-CD20 (designated combo therapy) inhibited T1D development. Despite eliciting broader B-lymphocyte depletion, continuous combo therapy afforded no greater T1D protection than BAFFR-Fc alone. As previously observed, late disease stage initiated anti-CD20 mono-therapy did not inhibit T1D, and in this study was additionally found to be associated with development of drug blocking antibodies. Promisingly, NOD mice given transient late disease stage BAFFR-Fc mono-therapy were rendered T1D resistant. However, combo treatment abrogated the protective effect of transient BAFFR-Fc mono-therapy. NOD mice receiving transient BAFF blockade were characterized by an enrichment of regulatory B-lymphocytes (Bregs) that inhibit T1D development through IL-10 production, but this population is sensitive to deletion by anti-CD20 treatment. B-lymphocytes from transient BAFFR-Fc treated mice suppressed T-cell proliferation to a greater extent than those from controls. Proportions of B-lymphocytes expressing CD73, an ecto-enzyme operating in a pathway converting pro-inflammatory ATP to immunosuppresive adenosine, were also temporarily increased by transient BAFFR-Fc treatment, but not anti-CD20 therapy. These collective studies indicate transient BAFFR-Fc mediated B-lymphocyte depletion elicits long-term T1D protection by enriching Bregs that are deleted by anti-CD20 co-therapy.

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“…PBMCs were activated overnight with 10μg/ml CpG (Toll-like receptor 9 ligand, ODN 2006; InvivoGen, Toulouse, France) as previously described [16]. Phorbol 12-myristate 13-acetate (0.4μg/ml) and ionomycine (0.5μg/ml) were added for the last 4 hr of culture and brefeldin A (10μg/ml) for the last 2 hr of culture.…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells

Audo

Hua

Hahne³

et al. 2017

PLoS ONE

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B cells can have a regulatory role, mainly mediated by interleukin 10 (IL-10). IL-10 producing B cells (B10 cells) cells remain to be better characterized. Annexin V binds phosphatidylserine (PS), which is externalized during apoptosis. Previous works suggested that B10 cells are apoptotic cells since they bind Annexin V. Others showed that Annexin V binding could also be expressed on viable B cells. We aimed to explore if PS exposure can be a marker of B10 cells and if PS exposure has a functional role on B cell IL-10 production in healthy subjects. We found that B10 cells were significantly more often Annexin V+ than IL-10 non-producing B cells. After CpG activation, Annexin V+ B cells differentiated more often into B10 cells than Annexin Vneg B cells. Cell death and early apoptosis were similar between Annexin V+ and Annexin Vneg B cells. PS blockage, using biotinylated AnV and glyburide, decreased B10 cell differentiation. This study showed that B10 cells have an increased PS exposure independently of any apoptotic state. B cells exposing PS differentiate more into B10 cells whereas PS blockage inhibits B10 cells generation. These results strongly suggest a link between PS exposure and B10 cells.

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A proliferation inducing ligand (APRIL) promotes IL-10 production and regulatory functions of human B cells

Cited by 60 publications

References 23 publications

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

Transient BAFF Blockade Inhibits Type 1 Diabetes Development in Nonobese Diabetic Mice by Enriching Immunoregulatory B Lymphocytes Sensitive to Deletion by Anti-CD20 Cotherapy

Phosphatidylserine Outer Layer Translocation Is Implicated in IL-10 Secretion by Human Regulatory B Cells

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