How MR1 Presents a Pathogen Metabolic Signature to Mucosal-Associated Invariant T (MAIT) Cells

Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes restricted by the antigen (Ag)-presenting molecule MHC class I (MHC I)-related protein 1 (MR1). The Ags presented by MR1 are vitamin B-related Ags (VitBAgs), 'building-block' metabolites of riboflavin that are synthesized by a range of microbes. MR1 presentation is thus a unique mechanism for the immune detection of a pathogen metabolic signature. While the full picture of how MR1 accomplishes this remains incomplete, recent data show that, unlike other MHC molecules, MR1 operates by a presentation-on-demand mechanism. In the absence of metabolite ligands MR1 is mostly stored in the endoplasmic reticulum (ER). Ligand binding leads to the formation of a Schiff-base bond between MR1 and its ligand, triggering a 'molecular switch' in MR1 that allows trafficking of the complexes to the cell surface. The complexes are subsequently internalized and mostly degraded irrespective of the affinity of the interaction between MR1 and its ligands. Here we review past and recent studies that have contributed to defining this pathway and propose new directions for a full understanding of the role and mechanisms of MR1 Ag presentation.