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

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 () and David P. Fairlie ()
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Jeffrey Y. W. Mak: Institute for Molecular Bioscience, The University of Queensland
Weijun Xu: Institute for Molecular Bioscience, The University of Queensland
Robert C. Reid: Institute for Molecular Bioscience, 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
James McCluskey: Peter Doherty Institute for Infection and Immunity, University of Melbourne
Ligong Liu: Institute for Molecular Bioscience, The University of Queensland
David P. Fairlie: Institute for Molecular Bioscience, The University of Queensland

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14599

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