Diverse T Cell receptor gene usage in HLA-DQ8-associated celiac disease converges into a consensus binding solution

In HLA-DQ8-associated celiac disease, TRAV26-2⁺-TRBV9⁺ and TRAV8-3⁺-TRBV6⁺ T cells recognize the immunodominant DQ8-glia-α1 epitope, whereupon a non-germline-encoded arginine residue played a key role in binding HLA-DQ8-glia-α1. Whether distinct T cell receptor (TCR) recognition modes exist for gliadin epitopes remains unclear. TCR repertoire analysis revealed populations of HLA-DQ8-glia-α1 and HLA-DQ8.5-glia-γ1 restricted TRAV20⁺-TRBV9⁺ T cells that did not possess a non-germline-encoded arginine residue. The crystal structures of a TRAV20⁺-TRBV9⁺ TCR-HLA-DQ8-glia-α1 complex and two TRAV20⁺-TRBV9⁺ TCR-HLA-DQ8.5-glia-γ1 complexes were determined. This revealed that the differential specificity toward DQ8-glia-α1 and DQ8.5-glia-γ1 was governed by CDR3β-loop-mediated interactions. Surprisingly, a germline-encoded arginine residue within the CDR1α loop of the TRAV20⁺ TCR substituted for the role of the non-germline-encoded arginine in the TRAV26-2⁺-TRBV9⁺ and TRAV8-3⁺-TRBV6⁺ TCRs. Thus, in celiac disease, the responding TCR repertoire is driven by a common mechanism that selects for structural elements within the TCR that have convergent binding solutions in HLA-DQ8-gliadin recognition.