Atypical TRAV1-2² T cell receptor recognition of the antigen-presenting molecule MR1

MR1 presents vitamin B-related metabolites to mucosal associated invariant T (MAIT) cells, which are characterized, in part, by the TRAV1-2¹ ab T cell receptor (TCR). In addition, a more diverse TRAV1-2² MR1-restricted T cell repertoire exists that can possess altered specificity for MR1 antigens. However, the molecular basis of how such TRAV1-2² TCRs interact with MR1-antigen complexes remains unclear. Here, we describe how a TRAV12-2¹ TCR (termed D462-E4) recognizes an MR1-antigen complex. We report the crystal structures of the unliganded D462-E4 TCR and its complex with MR1 presenting the riboflavin-based antigen 5-OP-RU. Here, the TRBV29-1 b-chain of the D462-E4 TCR binds over the F9-pocket of MR1, whereby the complementarity-determining region (CDR) 3b loop surrounded and projected into the F9-pocket. Nevertheless, the CDR3b loop anchored proximal to the MR1 A9-pocket and mediated direct contact with the 5-OP-RU antigen. The D462-E4 TCR footprint on MR1 contrasted that of the TRAV1-2¹ and TRAV36¹ TCRs' docking topologies on MR1. Accordingly, diverse MR1-restricted T cell repertoire reveals differential docking modalities on MR1, thus providing greater scope for differing antigen specificities.