Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms14599
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Funding
- Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging [CE140100011]
- National Health and Medical Research Council of Australia (NHMRC) [1016629, 606788, 1125493]
- ARC Laureate Fellowship [FL160100049]
- NHMRC Senior Principal Research Fellowships [1027369, 1117017]
- Australian Research Council [FL160100049] Funding Source: Australian Research Council
- National Health and Medical Research Council of Australia [1125493] Funding Source: NHMRC
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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 inverted perpendicular 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 MAITcells in human PBMCs, and stimulates cytokine expression (IFN gamma, 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.
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