Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease

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-alpha-I-gliadin. The structure of a prototypical TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDRbeta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9( *)01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the Vbeta 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.