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

Mak, Jeffrey Y. W., Xu, Weijun, Reid, Robert C., Corbett, Alexandra J., Meehan, Bronwyn S., Wang, Huimeng, Chen, Zhenjun, Rossjohn, Jamie, McCluskey, James, Liu, Ligong and Fairlie, David P. (2017) Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells. Nature Communications, 8 . doi:10.1038/ncomms14599

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Author Mak, Jeffrey Y. W.
Xu, Weijun
Reid, Robert C.
Corbett, Alexandra J.
Meehan, Bronwyn S.
Wang, Huimeng
Chen, Zhenjun
Rossjohn, Jamie
McCluskey, James
Liu, Ligong
Fairlie, David P.
Title Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2017-03-08
Year available 2017
Sub-type Article (original research)
DOI 10.1038/ncomms14599
Open Access Status DOI
Volume 8
Total pages 13
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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