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D-mannose induces regulatory T cells and suppresses immunopathology

Nature Medicine volume 23, pages 1036–1045 (2017)Cite this article

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Abstract

D-mannose, a C-2 epimer of glucose, exists naturally in many plants and fruits, and is found in human blood at concentrations less than one-fiftieth of that of glucose. However, although the roles of glucose in T cell metabolism, diabetes and obesity are well characterized, the function of D-mannose in T cell immune responses remains unknown. Here we show that supraphysiological levels of D-mannose safely achievable by drinking-water supplementation suppressed immunopathology in mouse models of autoimmune diabetes and airway inflammation, and increased the proportion of Foxp3+ regulatory T cells (Treg cells) in mice. In vitro, D-mannose stimulated Treg cell differentiation in human and mouse cells by promoting TGF-β activation, which in turn was mediated by upregulation of integrin αvβ8 and reactive oxygen species generated by increased fatty acid oxidation. This previously unrecognized immunoregulatory function of D-mannose may have clinical applications for immunopathology.

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Figure 1: D-mannose induces Treg cell differentiation in vitro and in vivo.
Figure 2: D-mannose induces Treg cell differentiation via activation of TGF-β.
Figure 3: Integrin αvβ8 and ROS are required for D-mannose-mediated TGF-β1 activation and Treg cell generation.
Figure 4: D-mannose suppresses type 1 diabetes in NOD mice.
Figure 5: Treg cells and TGF-β are involved in D-mannose-mediated suppression of autoimmune diabetes in NOD mice.
Figure 6: D-mannose induces antigen-specific Treg cells and suppresses ovalbumin-induced airway inflammation in BALB/cJ mice.

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Acknowledgements

This research was supported by the Intramural Research Program of the NIH, NIDCR. We thank E. Shevach (NIAID, NIH, Bethesda, Maryland, USA) for providing the Itgb8f/fCD4-Cre mice, and C. Benoist and D. Mathis (Harvard Medical School, Boston, Massachusetts, USA) for providing the NOD-Foxp3DTR mice. We also thank the NIDCR flow cytometry core for support.

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Authors and Affiliations

  1. Mucosal Immunology Section, NIDCR, US National Institutes of Health, Bethesda, Maryland, USA

    Dunfang Zhang, Cheryl Chia, Xue Jiao, Wenwen Jin, Shimpei Kasagi, Ruiqing Wu, Joanne E Konkel, Hiroko Nakatsukasa, Peter Zanvit, Nathan Goldberg & WanJun Chen

  2. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Sichuan, China

    Dunfang Zhang, Ruiqing Wu & Qianming Chen

  3. Center for Reproductive Medicine, Shandong University, Jinan, China

    Xue Jiao & Zi-Jiang Chen

  4. Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China

    Lingyun Sun

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Contributions

D.Z. designed and performed most of the experiments, analyzed and interpreted the data, and contributed to the writing of the manuscript. C.C. and X.J. designed and conducted experiments, analyzed data, and contributed to the writing of the manuscript. S.K., R.W., J.E.K., H.N., P.Z., N.G. and W.J. performed experiments. Q.C., L.S. and Z.-J.C. provided support and/or critical scientific input. W.J.C. conceived of and directed the research, designed the experiments, and wrote the paper.

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Correspondence to WanJun Chen.

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Zhang, D., Chia, C., Jiao, X. et al. D-mannose induces regulatory T cells and suppresses immunopathology. Nat Med 23, 1036–1045 (2017). https://doi.org/10.1038/nm.4375

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