The intracellular pathway for MR1 presentation of vitamin B-related antigens

Compounds related to Vitamin B metabolism (“VitB Ags”) produced by pathogens were recently discovered as a novel family of Ags that are presented by the MHC-I like molecule, MR1, to Mucosal-Associated Invariant T (MAIT) cells. In stark contrast with the mechanisms involved in presentation pathways for peptide and lipid Ags by MHC and CD1 molecules, respectively, the MR1 presentation pathway for VitB Ags remains largely uncharacterized. We show that MR1 does not constitutively present self-ligands in the steady-state, but accumulates in a ligand-receptive conformation within the endoplasmic reticulum (ER). Exogenous VitB Ags reach the ER, where they form a Schiff base with a lysine residue in the MR1 Ag-binding cleft. Formation of this covalent bond serves as a “molecular switch” that allows complete folding and egress of MR1-VitB Ag complexes out of the ER. The MR1-Ag complexes follow the secretory pathway, whereupon their half-life on the plasma membrane is independent of the affinity of the bound ligand. They undergo endocytosis and although some MR1 molecules acquire new ligands during passage through endosomes and recycle back to the surface, most are degraded intracellularly. Presentation of VitB Ags on the plasma membrane of MR1 antigen presenting cells thus decreases rapidly after the cells are no longer exposed to the ligand. In summary, the MR1 Ag presentation pathway possesses two main features that set it apart from the MHC and CD1 presentation pathways: (i) it presents exogenous VitB Ags but binding of these antigens to MR1 occurs within the ER rather than in the endocytic route; (ii) It is characterized by a rapid “off-on-off” mechanism strictly dependent on Ag availability.