Diverse T Cell Receptor Gene Usage in HLA-DQ8-Associated Celiac Disease Converges into a Consensus Binding Solution

作者：Petersen Jan; Kooy Winkelaar Yvonne; Loh Khai Lee; Mai Tran; Van Bergen Jeroen; Koning Frits; Rossjohn Jamie; Reid Hugh H

来源：Structure, 2016, 24(10): 1643-1657.

DOI：10.1016/j.str.2016.07.010

In HLA-DQ8-associated celiac disease, TRAV26-2(+)-TRBV9(+) and TRAV8-3(+)-TRBV6(+) T cells recognize the immunodominant DQ8-glia-alpha 1 epitope, whereupon a non-germline-encoded arginine residue played a key role in binding HLA-DQ8-glia-alpha 1. Whether distinct T cell receptor (TCR) recognition modes exist for gliadin epitopes remains unclear. TCR repertoire analysis revealed populations of HLA-DQ8-glia-alpha 1 and HLA-DQ8.5-glia-gamma 1 restricted TRAV20(+)-TRBV9(+) T cells that did not possess a non-germline-encoded arginine residue. The crystal structures of a TRAV20(+)-TRBV9(+) TCR-HLA-DQ8glia-alpha 1 complex and two TRAV20(+)-TRBV9(+) TCRHLA-DQ8.5-glia-gamma 1 complexes were determined. This revealed that the differential specificity toward DQ8-glia-alpha 1 and DQ8.5-glia-gamma 1 was governed by CDR3b-loop-mediated interactions. Surprisingly, a germline-encoded arginine residue within the CDR1 alpha 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.

• 出版日期2016-10-4