Dataset Information

Recognition of the antigen-presenting molecule MR1 by a Vδ3⁺ γδ T cell receptor.

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.

SUBMITTER: Rice MT

PROVIDER: S-EPMC8694053 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Recognition of the antigen-presenting molecule MR1 by a Vδ3+ γδ T cell receptor.

Rice Michael T MT von Borstel Anouk A Chevour Priyanka P Awad Wael W Howson Lauren J LJ Littler Dene R DR Gherardin Nicholas A NA Le Nours Jérôme J Giles Edward M EM Berry Richard R Godfrey Dale I DI Davey Martin S MS Rossjohn Jamie J Gully Benjamin S BS

Proceedings of the National Academy of Sciences of the United States of America 20211201 49

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 ...[more]

PMID: 34845016

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Project description:BackgroundT cell receptors (TCRs) can recognize diverse lipid and metabolite antigens presented by MHC-like molecules CD1 and MR1, and the molecular basis of many of these interactions has not been determined. Here we applied our protein docking algorithm TCRFlexDock, previously developed to perform docking of TCRs to peptide-MHC (pMHC) molecules, to predict the binding of αβ and γδ TCRs to CD1 and MR1, starting with the structures of the unbound molecules.ResultsEvaluating against TCR-CD1d complexes with crystal structures, we achieved near-native structures in the top 20 models for two out of four cases, and an acceptable-rated prediction for a third case. We also predicted the structure of an interaction between a MAIT TCR and MR1-antigen that has not been structurally characterized, yielding a top-ranked model that agreed remarkably with a characterized TCR-MR1-antigen structure that has a nearly identical TCR α chain but a different β chain, highlighting the likely dominance of the conserved α chain in MR1-antigen recognition. Docking performance was improved by re-training our scoring function with a set of TCR-pMHC complexes, and for a case with an outlier binding mode, we found that alternative docking start positions improved predictive accuracy. We then performed unbound docking with two mycolyl-lipid specific TCRs that recognize lipid-bound CD1b, which represent a class of interactions that is not structurally characterized. Highly-ranked models of these complexes showed remarkable agreement between their binding topologies, as expected based on their shared germline sequences, while differences in residue-level interactions with their respective antigens point to possible mechanisms underlying their distinct specificities.ConclusionsTogether these results indicate that flexible docking simulations can provide accurate models and atomic-level insights into TCR recognition of MHC-like molecules presenting lipid and other small molecule antigens.

Dataset Information

Recognition of the antigen-presenting molecule MR1 by a Vδ3⁺ γδ T cell receptor.

Publications

Recognition of the antigen-presenting molecule MR1 by a Vδ3<sup>+</sup> γδ T cell receptor.

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