A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1

T cell receptors (TCRs) recognize antigens presented by major histocompatibility complex (MHC) and MHC class I-like molecules. We describe a diverse population of human gamma delta T cells isolated from peripheral blood and tissues that exhibit autoreactivity to the monomorphic MHC-related protein 1 (MR1). The crystal structure of a gamma delta TCR-MR1-antigen complex starkly contrasts with all other TCR-MHC and TCR-MHC-I-like complex structures. Namely, the gamma delta TCR binds underneath the MR1 antigen-binding cleft, where contacts are dominated by the MR1 alpha 3 domain. A similar pattern of reactivity was observed for diverse MRl-restricted gamma delta TCRs from multiple individuals. Accordingly, we simultaneously report MR1 as a ligand for human gamma delta T cells and redefine the parameters for TCR recognition.