Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil

Lisa Ciacchi; Jeffrey Y W Mak; Jeremy P Le; David P Fairlie; James McCluskey; Alexandra J Corbett; Jamie Rossjohn; Wael Awad

doi:10.1016/j.jbc.2024.107229

Mouse mucosal-associated invariant T cell receptor recognition of MR1 presenting the vitamin B metabolite, 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil

J Biol Chem. 2024 Mar 25;300(5):107229. doi: 10.1016/j.jbc.2024.107229. Online ahead of print.

Authors

Lisa Ciacchi¹, Jeffrey Y W Mak², Jeremy P Le³, David P Fairlie², James McCluskey³, Alexandra J Corbett³, Jamie Rossjohn⁴, Wael Awad⁵

Affiliations

¹ Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
² Centre for Chemistry and Drug Discovery and ARC Centre of Excellence for Innovations in Peptide and Protein Science, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
³ Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.
⁴ Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: jamie.rossjohn@monash.edu.
⁵ Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. Electronic address: wael.awad@monash.edu.

Abstract

Mucosal-associated invariant T (MAIT) cells can elicit immune responses against riboflavin-based antigens presented by the evolutionary conserved MHC class I related protein, MR1. While we have an understanding of the structural basis of human MAIT cell receptor (TCR) recognition of human MR1 presenting a variety of ligands, how the semi-invariant mouse MAIT TCR binds mouse MR1-ligand remains unknown. Here, we determine the crystal structures of 2 mouse TRAV1-TRBV13-2⁺ MAIT TCR-MR1-5-OP-RU ternary complexes, whose TCRs differ only in the composition of their CDR3β loops. These mouse MAIT TCRs mediate high affinity interactions with mouse MR1-5-OP-RU and cross-recognize human MR1-5-OP-RU. Similarly, a human MAIT TCR could bind mouse MR1-5-OP-RU with high affinity. This cross-species recognition indicates the evolutionary conserved nature of this MAIT TCR-MR1 axis. Comparing crystal structures of the mouse versus human MAIT TCR-MR1-5-OP-RU complexes provides structural insight into the conserved nature of this MAIT TCR-MR1 interaction and conserved specificity for the microbial antigens, whereby key germline-encoded interactions required for MAIT activation are maintained. This is an important consideration for the development of MAIT cell-based therapeutics that will rely on preclinical mouse models of disease.

Keywords: 5-OP-RU; MHC-related molecule (MR1); antigen presentation; mouse MAIT TCR; protein structure.

Grants and funding

R01 AI148407/AI/NIAID NIH HHS/United States