National Academy of Sciences, Proceedings of the National Academy of Sciences, 49(118), 2021
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SignificanceAlongside 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.