Recognition of the antigen-presenting molecule MR1 by a Vd(3+) delta d T cell receptor

Unlike conventional alpha beta T cells, gamma delta T cells typically recognize non-peptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the gamma delta T cell receptor (TCR) can potentially recognize a wide array of ligands; however, few ligands have been described to date. While there is a growing appreciation of the molecular bases underpinning variable (V)delta 1(+) and V delta 2(+) gamma delta TCR-mediated ligand recognition, the mode of Vd3(+) TCR ligand engagement is unknown. MHC class I-related protein, MR1, presents vitamin B metabolites to alpha beta T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human gamma delta T cells. Here, we identify Vd1/2(-) gamma delta T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vd3V gamma 8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vd3V gamma 8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vd3 TCR chain that mediated specific contacts to the side of the MR1 antigen-binding groove, representing a previously uncharacterized MR1 docking topology. The binding of the Vd3(+) TCR to MR1 did not involve contacts with the presented antigen, providing a basis for understanding its inherent MR1 autoreactivity. We provide molecular insight into antigen-independent recognition of MR1 by a Vd3(+) gamma delta TCR that strengthens an emerging paradigm of antibody-like ligand engagement by gamma delta TCRs.