IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases

Shen, Ping; Roch, Toralf; Lampropoulou, Vicky; O’Connor, Richard A.; Stervbo, Ulrik; Hilgenberg, Ellen; Ries, Stefanie; Dang, Van Duc; Jaimes, Yarúa; Daridon, Capucine; Li, Rui; Jouneau, Luc; Boudinot, Pierre; Wilantri, Siska; Sakwa, Imme; Miyazaki, Yusei; Leech, Melanie D.; McPherson, Rhoanne C.; Wirtz, Stefan; Neurath, Markus F.; Hoehlig, Kai; Meinl, Edgar; Grützkau, Andreas; Grün, Joachim R.; Horn, Katharina; Kühl, Anja A.; Dörner, Thomas; Bar‐Or, Amit; Kaufmann, Stefan H. E.; Anderton, Stephen M.; Fillatreau, Simon

doi:10.1038/nature12979

Cited by 896 publications

(1,049 citation statements)

References 31 publications

Supporting

Mentioning

1,000

Contrasting

Unclassified

Order By: Relevance

“…7,23,43,58,59 In vitro-induced CD38 hi CD138 1 plasma cells were able to secrete large quantities of IL-10. These results are consistent with the work by Shen et al 29 and Matsumoto et al 31 who showed that CD138 1 plasma cells and plasmablast cells were the main IL-10 producers in mice with For personal use only. on April 2, 2019. by guest www.bloodjournal.org From experimental autoimmune encephalomyelitis.…”

Section: Discussionsupporting

confidence: 83%

“…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%

See 1 more Smart Citation

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

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 83%

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

146

119

View full text Add to dashboard Cite

show abstract

“…However, the recent study showed that IL-35-mediated negative regulation of immune responses is not restricted to CD4 1 CD25 1 Foxp3 1 T cells. 55 Some papers have reported that microRNA-containing or Fas ligand-expressing exosomes from Tregs or other tissues could mediate effector T-cell apoptosis. [56][57][58] Taken together, CD4 1 VEGFR1 high T-cell-mediated suppression might be exerted in various ways depending on the microenvironment, so that further studies to identify soluble factor(s) responsible for the suppressive activity should be considered under various circumstances.…”

Section: Discussionmentioning

confidence: 99%

CD4+VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice

et al. 2015

View full text Add to dashboard Cite

Regulatory T cells (Tregs) are a specialized subpopulation of T cells that control the immune response and thereby maintain immune system homeostasis and tolerance to self-antigens. Many subsets of CD4 1 Tregs have been identified, including Foxp3 1 , Tr1, Th3, and Foxp3neg iT(R)35 cells. In this study, we identified a new subset of CD4 1 VEGFR1 high Tregs that have immunosuppressive capacity. CD4 1 VEGFR1high T cells, which constitute approximately 1.0% of CD4 1 T cells, are hyporesponsive to T-cell antigen receptor stimulation. Surface marker and FoxP3 expression analysis revealed that CD4 1 VEGFR1 high T cells are distinct from known Tregs. CD4 1 VEGFR1 high T cells suppressed the proliferation of CD4 1 CD25 2 T cell as efficiently as CD4 1 CD25 high natural Tregs in a contact-independent manner. Furthermore, adoptive transfer of CD4 1 VEGFR1 1 T cells from wild type to RAG-2-deficient C57BL/6 mice inhibited effector T-cell-mediated inflammatory bowel disease. Thus, we report CD4 1 VEGFR1 high T cells as a novel subset of Tregs that regulate the inflammatory response in the intestinal tract.

show abstract

“…In addition to IL-10-producing regulatory B cells, another population of B-regulatory cells (and plasma cells) was found to express IL-35 and was able to downregulate T-cell responses. Knockout mice in which only B cells did not express IL-35 lost their ability to recover from EAE [95]. In another study, IgA + plasma cells were shown to produce TNF-α and inducible nitric oxide synthase, which enhance inflammatory responses in the local environment [96].…”

Section: B-cell Cytokines and B-cell/t-cell Interactions In Msmentioning

confidence: 99%

Neuroinflammation: Ways in Which the Immune System Affects the Brain

et al. 2015

Self Cite

View full text Add to dashboard Cite

Neuroinflammation is the response of the central nervous system (CNS) to disturbed homeostasis and typifies all neurological diseases. The main reactive components of the CNS include microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and the blood-brain b a r r i e r , c y t o k i n e s , a n d c y t o k i n e s i g n a l i n g . Neuroinflammatory responses may be helpful or harmful, as mechanisms associated with neuroinflammation are involved in normal brain development, as well as in neuropathological processes. This review examines the roles of various cell types that contribute to the immune dysregulation associated with neuroinflammation. Microglia enter the CNS very early in embryonic development and, as such, play an essential role in both the healthy and diseased brain. B-cell diversity contributes to CNS disease through both antibody-dependent and antibody-independent mechanisms. The influences of these B-cell mechanisms on other cell types, including myeloid cells and T cells, are reviewed in relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases.

show abstract

IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases

Cited by 896 publications

References 31 publications

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

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

CD4+VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice

Neuroinflammation: Ways in Which the Immune System Affects the Brain

Contact Info

Product

Resources

About