Stabilizing Short-lived Schiff Base Derivatives of 5-aminouracils That Activate Mucosal-associated Invariant T Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Mar 9

PMID 28272391

Citations 61

Authors

Jeffrey Y W Mak

Weijun Xu

Robert C Reid

Alexandra J Corbett

Bronwyn S Meehan

Huimeng Wang

Zhenjun Chen

Jamie Rossjohn

James McCluskey

Ligong Liu

David P Fairlie

Affiliations

Soon will be listed here.

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 1.5 h, 37 °C). Antigen solution structures, MAIT cell activation potencies (EC 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 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.

Citing Articles

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