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

SUMMARY 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 HLADQ8 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-a-I-gliadin. The structure of a prototypical TRBV9*01-TCR-HLA-DQ8-a-I-gliadin complex shows that the TCR docks centrally above HLADQ8-a-I-gliadin, in which all complementarity-determining region-b (CDRb) loops interact with the gliadin peptide. Mutagenesis at the TRBV9*01-TCRHLA-DQ8-a-I-gliadin interface provides an energetic basis for the Vb 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 DQ8mediated celiac disease.