Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease Academic Article uri icon

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.

authors

  • Broughton, Sophie E
  • Petersen, Jan
  • Theodossis, Alex
  • Scally, Stephen W
  • Loh, Khai Lee
  • Thompson, Allan
  • van Bergen, Jeroen
  • Kooy-Winkelaar, Yvonne
  • Henderson, Kate N
  • Beddoe, Travis
  • Tye-Din, Jason A
  • Mannering, Stuart I
  • Purcell, Anthony W
  • McCluskey, James
  • Anderson, Robert P
  • Koning, Frits
  • Reid, Hugh H
  • Rossjohn, Jamie

publication date

  • October 2012