Journal article

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

Jeffrey YW 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

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2017

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 ..

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Grants

Awarded by Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging


Awarded by National Health and Medical Research Council of Australia (NHMRC)


Awarded by ARC Laureate Fellowship


Awarded by NHMRC Senior Principal Research Fellowships


Funding Acknowledgements

We acknowledge support from the Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging (CE140100011) and the National Health and Medical Research Council of Australia (NHMRC) through program (1016629, 606788) and project (1125493) grants. J.R. was supported by an ARC Laureate Fellowship (FL160100049). D.P.F. was supported by NHMRC Senior Principal Research Fellowships (1027369, 1117017). We thank Dr Wei-Jen Chua and Dr Ted Hansen for kindly providing the 26.5 mAb.