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Regulatory B cells are induced by gut microbiota–driven interleukin-1β and interleukin-6 production

Nature Medicine volume 20, pages 1334–1339 (2014)Cite this article

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Abstract

Regulatory B cells (Breg cells) differentiate in response to inflammation and subsequently restrain excessive immune responses via the release of interleukin-10 (IL-10)1. However, the precise inflammatory signals governing their differentiation remain to be elucidated. Here we show that the gut microbiota promotes the differentiation of Breg cells in the spleen as well as in the mesenteric lymph nodes. Perturbation of the gut microbiome imposed either by antibiotic treatment or by changes in the sterility of housing conditions reduces the number and function of Breg cells. Following the induction of arthritis, IL-1β and IL-6 are produced only in conventionally housed mice and both cytokines directly promote Breg cell differentiation and IL-10 production. Mice lacking IL-6 receptor (IL-6R) or IL-1 receptor 1 (IL-1R1) specifically on B cells have a reduced number of IL-10–producing B cells and develop exacerbated arthritis compared to control animals. Thus, in response to inflammatory signals induced by both the gut flora and arthritis, Breg cells increase in number and restrain excessive inflammation.

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Figure 1: Impaired Breg cell function in mice treated with antibiotics.
Figure 2: Breg cells from mice housed in an SPF facility have impaired function.
Figure 3: IL-1β and IL-6 induce the differentiation of IL-10–producing B cells.
Figure 4: Breg cells are present in the mesenteric lymph nodes of inflamed mice and exhibit suppressive function.

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Acknowledgements

This work is funded by an Arthritis Research United Kingdom programme grant (MP/17707) awarded to C.M. E.C.R. is funded by an Arthritis Research United Kingdom PhD studentship (MP/19314) also awarded to C.M. R.D. is funded by a Food and Nutritional Technical Assistance III project (FANTA III). S.T. is funded by an Erasmus Placement programme (Consorzio KTEU EP6). We would like to thank the University College London Biological Service Unit staff for all their help controlling animal husbandry, J. Evans for cell sorting, K. Nistala for comments and P. Blair for critically reviewing the manuscript.

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Author notes

  1. Natalie A Carter

    Present address: Present address: Arthritis Research UK, London, UK.,

Authors and Affiliations

  1. Division of Medicine, Centre for Rheumatology, University College London, London, UK

    Elizabeth C Rosser, Kristine Oleinika, Anneleen Bosma, Natalie A Carter & Claudia Mauri

  2. Dipartimento di Medicina e Scienze Biologiche, Universita' degli Studi di Udine, Udine, Italia

    Silvia Tonon

  3. Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, UK

    Ronan Doyle & Nigel Klein

  4. Department of Microbiology, Virology and Infection Control, Great Ormond Street Hospital National Health Service Foundation Trust, London, UK

    Kathryn A Harris

  5. Cardiff Institute for Infection & Immunity, The School of Medicine, Cardiff University, Cardiff, Wales, UK.,

    Simon A Jones

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Contributions

C.M. and E.C.R. designed and conceived the experiments. E.C.R. performed the experiments. C.M., S.T., A.B. and N.A.C. helped with large in vivo experiments. K.O. helped with signaling experiments. R.D., K.A.H. and N.K. analyzed fecal samples. C.M. and E.C.R. wrote and prepared the manuscript. S.A.J. provided Il6r−/− mice.

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Correspondence to Claudia Mauri.

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The authors declare no competing financial interests.

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Rosser, E., Oleinika, K., Tonon, S. et al. Regulatory B cells are induced by gut microbiota–driven interleukin-1β and interleukin-6 production. Nat Med 20, 1334–1339 (2014). https://doi.org/10.1038/nm.3680

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