The Immune system is our principle defense in a constant battle against pathogenic organisms. A fundamental process in our ability to mount a successful immune response is the ability of T lymphocytes (T cells) to survey our bodies for signs of infection. Key to a successful T cell response is recognition of a suitable foreign antigen by the T cell receptor (TCR) and initiation of a signaling cascade that sacrifices the infected cell to prevent further pathogenic spread.

Classical antigen presentation is performed by the major histocompatibity complexes (MHC), presenting short peptide sequences to the T cell receptor for immune surveillance. Recently our work has redefined our knowledge of what constitutes a T cell antigen, expanding our known antigenic repertoire from classical peptides and lipid immunity to include vitamin metabolites. The MHC class 1b related molecule MR1, which is ubiquitously expressed, mediates this novel presentation and is restricted to the mucosal associated invariant T (MAIT) cell subclass.

We identified 5-amino-6-d-ribitylaminouracil (5-A-RU) from the bacterial riboflavin (vitamin B2) biosynthesis pathway as a biosynthesis intermediate essential for activation of MAIT cells¹. Surprisingly, elucidation of crystal structures of MR1 bound to 5-A-RU and the MAIT TCR revealed that 5-A-RU had been tailored by methylglyoxal, a small reactive byproduct from glycolysis, forming 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU).  5-OP-RU was shown to be unstable in solution and was stabilized within MR1 by forming a covalent Schiff base to a lysine residue from MR1 and allowing an enhanced MAIT cell response. The crystal structure combined with cellular and single molecule binding assays has provided insight to how MAIT cells are specifically activated by 5-OP-RU in response to infection.

Detection of riboflavin biosynthesis intermediates by MAIT cells represents a new class of antigens and novel immune process that has redefined the dogma of T cell antigen recognition.