Significance
Alongside αβ T cells and B cells, γδ T cells comprise a major component of the adaptive immune system, although a lack of bona fide ligands has hindered understanding of their function. γδ T cells are key mediators of epithelial immune surveillance and have a purported capacity for employing diverse ligand engagement mechanisms beyond the dogmas of conventional αβ T cell–human leukocyte antigen restriction. Here, we found blood- and gut-resident Vδ1/2− γδ T cells bound to MR1 tetramers in a metabolite-independent mechanism distinct from mucosal-associated invariant T cells and provide insight into a unique antibody-like MR1 recognition mode. This reshapes our understanding of the ligand recognition principles of γδ T cells and how they differ from αβ T cells.
Abstract
Unlike conventional αβ T cells, γδ T cells typically recognize nonpeptide ligands independently of major histocompatibility complex (MHC) restriction. Accordingly, the γδ 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)δ1+ and Vδ2+ γδ TCR-mediated ligand recognition, the mode of Vδ3+ TCR ligand engagement is unknown. MHC class I–related protein, MR1, presents vitamin B metabolites to αβ T cells known as mucosal-associated invariant T cells, diverse MR1-restricted T cells, and a subset of human γδ T cells. Here, we identify Vδ1/2− γδ T cells in the blood and duodenal biopsy specimens of children that showed metabolite-independent binding of MR1 tetramers. Characterization of one Vδ3Vγ8 TCR clone showed MR1 reactivity was independent of the presented antigen. Determination of two Vδ3Vγ8 TCR-MR1-antigen complex structures revealed a recognition mechanism by the Vδ3 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 Vδ3+ 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 Vδ3+ γδ TCR that strengthens an emerging paradigm of antibody-like ligand engagement by γδ TCRs.
