Chancellery Research - Research Publications

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Start date: 2017 × End date: 2017 × Author: Corbett, Alexandra × Author: Chen, Zhenjun ×

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    Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells
    Keller, AN ; Eckle, SBG ; Xu, W ; Liu, L ; Hughes, VA ; Mak, JYW ; Meehan, BS ; Pediongco, T ; Birkinshaw, RW ; Chen, Z ; Wang, H ; D'Souza, C ; Kjer-Nielsen, L ; Gherardin, NA ; Godfrey, DI ; Kostenko, L ; Corbett, AJ ; Purcell, AW ; Fairlie, DP ; McCluskey, J ; Rossjohn, J (NATURE PUBLISHING GROUP, 2017-04)
    The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals.
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    Stabilizing short-lived Schiff base derivatives of 5-aminouracils that activate mucosal-associated invariant T cells
    Mak, JYW ; Xu, W ; Reid, RC ; Corbett, AJ ; Meehan, BS ; Wang, H ; Chen, Z ; Rossjohn, J ; McCluskey, J ; Liu, L ; Fairlie, DP (NATURE PUBLISHING GROUP, 2017-03-08)
    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.