Biased T Cell Receptor Usage Directed Against Human Leukocyte Antigen DQ8-restricted Gliadin Peptides Is Associated With Celiac Disease

Immunity. 2012 Oct 19;37(4):611-21. doi: 10.1016/j.immuni.2012.07.013. Epub 2012 Oct 11.

Abstract

Celiac disease is a human leukocyte antigen (HLA)-DQ2- and/or DQ8-associated T cell-mediated disorder that is induced by dietary gluten. Although it is established how gluten peptides bind HLA-DQ8 and HLA-DQ2, it is unclear how such peptide-HLA complexes are engaged by the T cell receptor (TCR), a recognition event that triggers disease pathology. We show that biased TCR usage (TRBV9(∗)01) underpins the recognition of HLA-DQ8-α-I-gliadin. The structure of a prototypical TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-α-I-gliadin, in which all complementarity-determining region-β (CDRβ) loops interact with the gliadin peptide. Mutagenesis at the TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin interface provides an energetic basis for the Vβ bias. Moreover, CDR3 diversity accounts for TRBV9(∗)01(+) TCRs exhibiting differing reactivities toward the gliadin epitopes at various deamidation states. Accordingly, biased TCR usage is an important factor in the pathogenesis of DQ8-mediated celiac disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Celiac Disease / immunology*
  • Epitopes, T-Lymphocyte / immunology
  • Gliadin / immunology*
  • HLA-DQ Antigens / chemistry
  • HLA-DQ Antigens / immunology*
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptide Fragments / immunology
  • Protein Interaction Domains and Motifs
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Peptide Fragments
  • Receptors, Antigen, T-Cell
  • Gliadin