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Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions

Nature volume 491, pages 264–268 (2012)Cite this article

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Abstract

B cells regulate immune responses by producing antigen-specific antibodies1. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells2,3,4. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified2,3,4,5. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice5,6,7. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.

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Figure 1: IL-21 induces regulatory B10-cell function.
Figure 2: B10 cells require IL-10, IL-21R, CD40 and MHC-II expression to regulate EAE severity.
Figure 3: B10-cell expansion and regulation of T-cell-mediated autoimmunity.
Figure 4: IL-21 drives ex vivo regulatory B10-cell expansion.

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Acknowledgements

We thank D. Maseda, E. Weimer, J. Bryant, K. Candando and G. Venturi for help and comments. These studies were supported by grants from the National Institutes of Health (NIH; AI56363 and AI057157), the Lymphoma Research Foundation, and the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH.

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Author notes

  1. Ayumi Yoshizaki, Tomomitsu Miyagaki and Thomas F. Tedder: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Immunology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Ayumi Yoshizaki, Tomomitsu Miyagaki, David J. DiLillo, Takashi Matsushita, Mayuka Horikawa, Evgueni I. Kountikov, Jonathan C. Poe & Thomas F. Tedder

  2. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, 20892-1674, Maryland, USA

    Rosanne Spolski & Warren J. Leonard

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  1. Ayumi Yoshizaki
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Contributions

A.Y., T.Mi., D.J.D., T.Ma., M.H., J.C.P., W.J.L. and T.F.T. conceived and designed the studies. A.Y., T.Mi., D.J.D., T.Ma., M.H., E.I.K., R.S., J.C.P. and W.J.L. carried out or contributed essential reagents and materials for the experiments. All authors contributed to data analysis and manuscript preparation.

Corresponding author

Correspondence to Thomas F. Tedder.

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Competing interests

T.F.T. is a consultant and shareholder for Angelica Therapeutics, Inc. R.S. and W.J.L. are inventors on patents and patent applications related to IL-21. The other authors have no financial conflicts of interest.

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Yoshizaki, A., Miyagaki, T., DiLillo, D. et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012). https://doi.org/10.1038/nature11501

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