Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28272391.
- Also identified by DOI 10.1038/ncomms14599 and PMC identifier 5344979.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 (t<sub>1/2</sub> 1.5 h, 37 °C). Antigen solution structures, MAIT cell activation potencies (EC<sub>50</sub> 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 (EC<sub>50</sub> 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.
Medical subject headings
- Lymphocyte Activation
- Mucosal-Associated Invariant T Cells
- Mucous Membrane
- Schiff Bases
- Uracil