Journal article

The molecular basis underpinning the potency and specificity of MAIT cell antigens

Wael Awad, Geraldine JM Ler, Weijun Xu, Andrew N Keller, Jeffrey YW Mak, Xin Yi Lim, Ligong Liu, Sidonia BG Eckle, Jerome Le Nours, James McCluskey, Alexandra J Corbett, David P Fairlie, Jamie Rossjohn

Nature Immunology | NATURE PUBLISHING GROUP | Published : 2020

Abstract

Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT-MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)-MR1-AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1-AML interfa..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging


Awarded by The University of Queensland


Funding Acknowledgements

We thank the staff at the National Synchrotron for assistance with data collection and the staff at the Monash Macromolecular Crystallization Facility and the Doherty Flow Cytometry Facility. This research was undertaken in part by using the MX2 beamline at the Australian Synchrotron, part of ANSTO, and made use of the Australian Cancer Research Foundation (ACRF) detector. This work was supported by the Australian National Health and Medical Research Council (NHMRC; 1125493 and 1113293), the Australian Research Council (ARC) Centre of Excellence in Advanced Molecular Imaging (CE140100011) and The University of Queensland (UQECR1834385). D.P.F. was an NHMRC Senior Principal Research Fellow (1027369 and 1117017), S.E. is an ARC DECRA Fellow (DE170100407), A.J.C. (FT160100083) and J.L.N. (FT160100074) are ARC Future Fellows and J.R. is an Australian ARC Laureate Fellow (FL160100049).