title: Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells.
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 (t1/21.5 h, 37 °C). Antigen solution structures, MAIT cell activation potencies (EC503-500 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 (EC502 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.
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Jeffrey Y W
authors.initials: JY
authors.lastname: Mak
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Weijun
authors.initials: W
authors.lastname: Xu
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Robert C
authors.identifier: 0000-0002-0829-239X
authors.initials: RC
authors.lastname: Reid
authors.affiliation: Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Alexandra J
authors.identifier: 0000-0003-1618-4337
authors.initials: AJ
authors.lastname: Corbett
authors.affiliation: Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Bronwyn S
authors.initials: BS
authors.lastname: Meehan
authors.affiliation: Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Huimeng
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Infection and Immunity Program &Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.|Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Microbiology &Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Ligong
authors.identifier: 0000-0002-2693-1896
authors.initials: L
authors.lastname: Liu
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.|Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
mesh_terms: D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology; D006019:Glycolysis; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D007371:Interferon-gamma / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D000072336:Mucosal-Associated Invariant T Cells / Q000187:drug effects* / Q000276:immunology; D009092:Mucous Membrane / Q000166:cytology*; D058849:Protein Refolding; D012545:Schiff Bases / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000941:Antigens; D015395:Histocompatibility Antigens Class I; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D012545:Schiff Bases; D014409:Tumor Necrosis Factor-alpha; D014498:Uracil; D007371:Interferon-gamma; C011166:5-aminouracil