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Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells

Author

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  • Jeffrey Y. W. Mak

    (Institute for Molecular Bioscience, The University of Queensland
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland)

  • Weijun Xu

    (Institute for Molecular Bioscience, The University of Queensland
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland)

  • Robert C. Reid

    (Institute for Molecular Bioscience, The University of Queensland
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland)

  • Alexandra J. Corbett

    (Peter Doherty Institute for Infection and Immunity, University of Melbourne)

  • Bronwyn S. Meehan

    (Peter Doherty Institute for Infection and Immunity, University of Melbourne)

  • Huimeng Wang

    (Peter Doherty Institute for Infection and Immunity, University of Melbourne)

  • Zhenjun Chen

    (Peter Doherty Institute for Infection and Immunity, University of Melbourne)

  • Jamie Rossjohn

    (Biomedicine Discovery Institute, Monash University
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University
    Institute of Infection and Immunity, Cardiff University, School of Medicine)

  • James McCluskey

    (Peter Doherty Institute for Infection and Immunity, University of Melbourne)

  • Ligong Liu

    (Institute for Molecular Bioscience, The University of Queensland
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland)

  • David P. Fairlie

    (Institute for Molecular Bioscience, The University of Queensland
    Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland)

Abstract

Mucosal-associated invariant T (MAIT) cells are activated by unstable antigens formed by reactions of 5-amino-6-D-ribitylaminouracil (a vitamin B2 biosynthetic intermediate) with glycolysis metabolites such as methylglyoxal. Here we show superior preparations of antigens in dimethylsulfoxide, avoiding their rapid decomposition in water (t1/2 1.5 h, 37 °C). Antigen solution structures, MAIT cell activation potencies (EC50 3–500 pM), and chemical stabilities are described. Computer analyses of antigen structures reveal stereochemical and energetic influences on MAIT cell activation, enabling design of a water stable synthetic antigen (EC50 2 nM). Like native antigens, this antigen preparation induces MR1 refolding and upregulates surface expression of human MR1, forms MR1 tetramers that detect MAIT cells in human PBMCs, and stimulates cytokine expression (IFNγ, TNF) by human MAIT cells. These antigens also induce MAIT cell accumulation in mouse lungs after administration with a co-stimulant. These chemical and immunological findings provide new insights into antigen properties and MAIT cell activation.

Suggested Citation

  • Jeffrey Y. W. Mak & Weijun Xu & Robert C. Reid & Alexandra J. Corbett & Bronwyn S. Meehan & Huimeng Wang & Zhenjun Chen & Jamie Rossjohn & James McCluskey & Ligong Liu & David P. Fairlie, 2017. "Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14599
    DOI: 10.1038/ncomms14599
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