The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins

Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1771-8. doi: 10.1073/pnas.1222678110. Epub 2013 Apr 23.


Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved αβ T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, cross-species reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 Å complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 α1 and α2 helices, similar to classical αβ TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the α-chain, focused on the MR1 α2 helix. TCR β-chain contacts are mostly through the variable CDR3β loop that is positioned proximal to the CDR3α loop directly over the MR1 open groove. The elucidation of the MAIT TCR/MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of αβ T-cell recognition of MHC and MHC-like ligands.

Keywords: antigen-presentation; metabolite; molecular recognition; unconventional T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation
  • Binding Sites
  • Cattle
  • Crystallography, X-Ray
  • Histocompatibility Antigens Class I / metabolism*
  • Humans
  • Ligands
  • Lymphocyte Activation
  • Minor Histocompatibility Antigens
  • Molecular Docking Simulation
  • Mutagenesis
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Recombinant Proteins / metabolism
  • T-Lymphocyte Subsets / metabolism*


  • Histocompatibility Antigens Class I
  • Ligands
  • MR1 protein, human
  • Minor Histocompatibility Antigens
  • Receptors, Antigen, T-Cell, alpha-beta
  • Recombinant Proteins

Associated data

  • PDB/4IIQ