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Cited by 1,048T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisCytokine Signaling Pathways and Interactions

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

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Shen, Ping, Roch, Toralf, Lampropoulou, Vicky, O’Connor, Richard A., Stervbo, Ulrik, Hilgenberg, Ellen, Ries, Stefanie, Dang, Van Duc +23 more·2014·Nature
DOI 10.1038/nature12979PMC PMC4260166
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Abstract

B lymphocytes have critical roles as positive and negative regulators of immunity. Their inhibitory function has been associated primarily with interleukin 10 (IL-10) because B-cell-derived IL-10 can protect against autoimmune disease and increase susceptibility to pathogens. Here we identify IL-35-producing B cells as key players in the negative regulation of immunity. Mice in which only B cells did not express IL-35 lost their ability to recover from the T-cell-mediated demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE). In contrast, these mice displayed a markedly improved resistance to infection with the intracellular bacterial pathogen Salmonella enterica serovar Typhimurium as shown by their superior containment of the bacterial growth and their prolonged survival after primary infection, and upon secondary challenge, compared to control mice. The increased immunity found in mice lacking IL-35 production by B cells was associated with a higher activation of macrophages and inflammatory T cells, as well as an increased function of B cells as antigen-presenting cells (APCs). During Salmonella infection, IL-35- and IL-10-producing B cells corresponded to two largely distinct sets of surface-IgM(+)CD138(hi)TACI(+)CXCR4(+)CD1d(int)Tim1(int) plasma cells expressing the transcription factor Blimp1 (also known as Prdm1). During EAE, CD138(+) plasma cells were also the main source of B-cell-derived IL-35 and IL-10. Collectively, our data show the importance of IL-35-producing B cells in regulation of immunity and highlight IL-35 production by B cells as a potential therapeutic target for autoimmune and infectious diseases. This study reveals the central role of activated B cells, particularly plasma cells, and their production of cytokines in the regulation of immune responses in health and disease.

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  • Bregs are B cells with regulatory and immunosuppressive functions that maintain immunological homeostasis by producing IL-10, IL-35, and TGFβ, thereby suppressing immunopathology.

    “Bregs is a generic term used to define B cells endowed with regulatory and immunosuppressive functions. They play a crucial role in maintain­ ing immunological homeostasis by producing anti-inflammatory cyto­ kines such as interleukin-10 (IL-10), IL-35, and transforming growth factor-beta (TGFβ ), thereby suppressing immunopathology.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [55]

    The Results & Discussion section describes B-cell suppression of autoimmune inflammation through IL-10 and identifies IL-35-producing B cells as regulators of immunity. It does not identify TGFβ as a cytokine produced by these regulatory B cells, so the three-cytokine account is only partly supported. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • Bregs inhibit the expansion of pathogenic T cells and other pro-inflammatory immune cells, thereby preventing excessive immune activation.

    “Bregs inhibit the expansion of pathogenic T cells and other pro-inflammatory immune cells, thereby preventing excessive immune activation [55 -58].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [55]

    In Results & Discussion (page not provided), IL-35-deficient B cells stimulated greater proliferation of MOG-reactive inflammatory T cells, supporting the T-cell part of the claim. The paper also reports greater macrophage activation when B cells lack IL-35, but does not show that Bregs inhibit the expansion of those other cells; its findings are in mouse models of EAE and Salmonella infection. (LLM, conf=0.86)

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Cited by

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Authors
Shen, P., Roch, T., Lampropoulou, V., O’Connor, R. A., Stervbo, U., Hilgenberg, E., Ries, S., Dang, V. D., Jaimes, Y., Daridon, C., Li, R., Jouneau, L., Boudinot, P., Wilantri, S., Sakwa, I., Miyazaki, Y., Leech, M. D., McPherson, R. C., Wirtz, S., Neurath, M., Hoehlig, K., Meinl, E., Grützkau, A., Grün, J. R., Horn, K., Kühl, A. A., Dörner, T., Bar-Or, A., Kaufmann, S. H. E., Anderton, S. M., & Fillatreau, S.
Affiliations
  • German Rheumatism Research Centre (DE)
  • Centre for Inflammation Research (GB)
  • Montreal Neurological Institute and Hospital (CA)
  • Virologie et Immunologie Moléculaires (FR)
  • Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
  • Institut für Klinische Neuroimmunologie (DE)
  • Max Planck Society (DE)
Corresponding author
Fillatreau, Simon
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2014-02-23
Volume
507
Issue
7492
Pages
366-370
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature12979
PMC
PMC4260166
OpenAlex
W1976302032
Cited by
1,048
References
1
Citations by year
2026: 58 · 2025: 52 · 2024: 62 · 2023: 75 · 2022: 81 · 2021: 100 · 2020: 94 · 2019: 113 · 2018: 87 · 2017: 83 · 2016: 89 · 2015: 109 · 2014: 43 · 2013: 1
FWCI
45.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Max Planck Digital Library (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • Wellcome Trust (087833, 095831)
  • Deutsche Forschungsgemeinschaft (TR‐128, FI‐1238/02, TRR-36, TRR130, SFB TR‐128, SFB 650)
  • Institut National de la Recherche Agronomique
  • Canadian Institutes of Health Research
  • Medical Research Council
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
IL-35, IL-10, B cells, plasma cells, experimental autoimmune encephalomyelitis, T cell-mediated autoimmunity, Salmonella typhimurium infection, intracellular bacterial infection, Blimp-1, antigen-presenting cells, macrophage activation, T cell activation, therapeutic target, autoimmunity, infectious disease resistance, syndecan-1
MeSH terms
Animals, Antigen-Presenting Cells, B-Lymphocytes, Encephalomyelitis, Autoimmune, Experimental, Female, Humans, Immunity, Interleukins, Lymphocyte Activation, Macrophages, Male, Plasma Cells, Salmonella Infections, T-Lymphocytes, Interleukin-10, CD40 Antigens, Toll-Like Receptor 4, Mice

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