7LLJ

Recognition of the antigen-presenting molecule MR1 by a V delta 3 + gamma delta T cell receptor.

(2021) Proc Natl Acad Sci U S A 118

• PubMed: 34845016 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.1073/pnas.2110288118
• Primary Citation of Related Structures:  
  7LLI, 7LLJ


• PubMed 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.

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Organizational Affiliation: 

Infection and Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.