Delivery of loaded MR1 monomer results in efficient ligand exchange to host MR1 and subsequent MR1T cell activation

Abstract

MR1 restricted T (MR1T) cells have the potential to be important players in microbial infections, sterile inflammation, wound healing and cancer. Similar to other antigen presentation molecules, evidence supports multiple, complementary MR1 antigen presentation pathways. To investigate post-ER pathways for MR1 loading, we used MR1 monomers and tetramers loaded with 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil (5-OP-RU) to deliver the antigen. Using MR1-deficient cells reconstituted with wild-type MR1 or MR1 molecules that cannot bind 5-OP-RU, we show that presentation of monomer-delivered 5-OPRU is dependent on host MR1 and requires the transfer of ligand from the soluble molecule onto MR1 expressed by the antigen presenting cell in post-ER compartments. We propose a model where chaperones direct the exchange of covalently bound ligands from one MR1 molecule to another. This new mode of ligand delivery strengthens the evidence for a post-ER exchange pathway for MR1, which could represent an important avenue by which MR1 acquires antigens derived from endocytosed pathogens.