Recognition of vitamin B metabolites by mucosal-associated invariant T cells

Onisha Patel, Lars Kjer-Nielsen, Jérôme Le Nours, Sidonia B. G. Eckle, Richard Birkinshaw, Travis Beddoe, Alexandra J. Corbett, Ligong Liu, John J. Miles, Bronwyn Meehan, Rangsima Reantragoon, Maria L. Sandoval-Romero, Lucy C. Sullivan, Andrew G. Brooks, Zhenjun Chen, David P. Fairlie, James McCluskey, Jamie Rossjohn

The mucosal-associated invariant T-cell antigen receptor (MAIT TCR) recognizes MR1 presenting vitamin B metabolites. Here we describe the structures of a human MAIT TCR in complex with human MR1 presenting a non-stimulatory ligand derived from folic acid and an agonist ligand derived from a riboflavin metabolite. For both vitamin B antigens, the MAIT TCR docks in a conserved manner above MR1, thus acting as an innate-like pattern recognition receptor. The invariant MAIT TCR α-chain usage is attributable to MR1-mediated interactions that prise open the MR1 cleft to allow contact with the vitamin B metabolite. Although the non-stimulatory antigen does not contact the MAIT TCR, the stimulatory antigen does. This results in a higher affinity of the MAIT TCR for a stimulatory antigen in comparison with a non-stimulatory antigen. We formally demonstrate a structural basis for MAIT TCR recognition of vitamin B metabolites, while illuminating how TCRs recognize microbial metabolic signatures.