From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets

Dang, Van Duc; Hilgenberg, Ellen; Ries, Stefanie; Shen, Ping; Fillatreau, Simon

doi:10.1016/j.coi.2014.02.009

Cited by 107 publications

(78 citation statements)

References 58 publications

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“…Interestingly, as already described for the pro-B10 regulatory cell population, this leads to the conclusion that B cell-mediated regulation is probably inducible and that the effect of B cells is greatly influenced by the nature of the microenvironment. 35,36,[38][39][40] The expression of IL-10 has been shown to be a frequent characteristic of Bregs. [41][42][43] Such cells, referred to as B10, 32,44 are involved in the initiation, the onset, and the severity of various autoimmune diseases, and in transplantation.…”

Section: Discussionmentioning

confidence: 99%

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Chesneau¹,

Michel²,

Dugast³

et al. 2015

Journal of the American Society of Nephrology

134

118

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Whereas a B cell-transcriptional profile has been recorded for operationally tolerant kidney graft patients, the role that B cells have in this tolerance has not been reported. In this study, we analyzed the role of B cells from operationally tolerant patients, healthy volunteers, and kidney transplant recipients with stable graft function on T cell suppression. Proliferation, apoptosis, and type I proinflammatory cytokine production by effector CD4 + CD25 2 T cells were measured after anti-CD3/anti-CD28 stimulation with or without autologous B cells. We report that B cells inhibit CD4 + CD25 2 effector T cell response in a dosedependent manner. This effect required B cells to interact with T-cell targets and was achieved through a granzyme B (GzmB)-dependent pathway. Tolerant recipients harbored a higher number of B cells expressing GzmB and displaying a plasma cell phenotype. Finally, GzmB + B-cell number was dependent on IL-21 production, and B cells from tolerant recipients but not from other patients positively regulated both the number of IL-21 + T cells and IL-21 production, suggesting a feedback loop in tolerant recipients that increases excessive B cell activation and allows regulation to take place. These data provide insights into the characterization of B cell-mediated immunoregulation in clinical tolerance and show a potential regulatory effect of B cells on effector T cells in blood from patients with operationally tolerant kidney grafts.

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Section: Discussionmentioning

confidence: 99%

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Chesneau¹,

Michel²,

Dugast³

et al. 2015

Journal of the American Society of Nephrology

134

118

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“…Regulatory B cells may be composed of cells with a heterogeneous phenotype and present at various steps of differentiation. Indeed, it has been suggested that regulatory B cells acquired their fully suppressive phenotype following reencounter with the specific Ags at the plasmablast/ plasma cell differentiation step by acting through the secretion of a high level of immunosuppressive cytokine such as IL-10 or IL-35 (9,12,38,39). We observed in a mouse skin graft model that LF15-0195 immunosuppressor induced during treatment a strong drop in the new T1 emigrants B cells in blood that were then restored following treatment cessation (E. Chiffoleau, unpublished results).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, characterization has relied exclusively on assessing their suppressive activity. Although several regulatory B cell subsets have been described in humans and mice, most of them share the ability to express the anti-inflammatory cytokine IL-10 and can be identified in the transitional immature, naive, CD27 + memory as well as the plasmablast/plasma B cell subpopulations (6)(7)(8)(9) (10)(11)(12)(13). We previously demonstrated a model of cardiac allograft tolerance in the rat induced by a short-term treatment with the immunosuppressor LF15-0195, a deoxyspergualin analog (14,15).…”

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confidence: 99%

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

Durand

Huchet

Mérieau

et al. 2015

The Journal of Immunology

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Emerging knowledge regarding B cells in organ transplantation has demonstrated that these cells can no longer be taken as mere generators of deleterious Abs but can also act as beneficial players. We previously demonstrated in a rat model of cardiac allograft tolerance induced by short-term immunosuppression an accumulation in the blood of B cells overexpressing inhibitory molecules, a phenotype also observed in the blood of patients that spontaneously develop graft tolerance. In this study, we demonstrated the presence in the spleen of regulatory B cells enriched in the CD24intCD38+CD27+IgD−IgM+/low subpopulation, which are able to transfer donor-specific tolerance via IL-10 and TGF-β1–dependent mechanisms and to suppress in vitro TNF-α secretion. Following anti-CD40 stimulation, IgD−IgM+/low B cells were blocked in their plasma cell differentiation pathway, maintained high expression of the inhibitory molecules CD23 and Bank1, and upregulated Granzyme B and Irf4, two molecules described as highly expressed by regulatory B cells. Interestingly, these B cells recognized specifically a dominant donor Ag, suggesting restricted specificity that could lead to a particular B cell response. Regulatory B cells were not required for induction of tolerance and appeared following Foxp3+CD4+CD25+ regulatory T cells, suggesting cooperation with regulatory T cells for their expansion. Nevertheless, following transfer to new recipients, these B cells migrated to the allograft, kept their regulatory profile, and promoted local accumulation of Foxp3+CD4+CD25+ regulatory T cells. Mechanisms of regulatory B cells and their cell therapy potential are important to decipher in experimental models to pave the way for future developments in the clinic.

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“…11 Recent studies have shown that the latter cell subset bears regulatory properties and may be the main IL-10-producing B-cell subset in mice. [28][29][30][31] Discrepancies in the cell surface antigens studied and a lack of consensual definitions of the subset phenotypes limit the direct comparison of human B-cell subpopulation analyses. It is generally admitted that most human memory B cells are characterized by the expression of CD27 [32][33][34][35] and that human plasmablasts display a CD20 lo CD24 2 CD27 hi CD38 hi phenotype.…”

Section: Introductionmentioning

confidence: 99%

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

140

114

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Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

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From the regulatory functions of B cells to the identification of cytokine-producing plasma cell subsets

Cited by 107 publications

References 58 publications

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Tolerant Kidney Transplant Patients Produce B Cells with Regulatory Properties

Regulatory B Cells with a Partial Defect in CD40 Signaling and Overexpressing Granzyme B Transfer Allograft Tolerance in Rodents

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

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