|4gg6, resolution 3.20Å ()|
|Gene:||HLA-DQA1 (Homo sapiens), HLA-DQB, HLA-DQB1 (Homo sapiens)|
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.
Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease., Broughton SE, Petersen J, Theodossis A, Scally SW, Loh KL, Thompson A, van Bergen J, Kooy-Winkelaar Y, Henderson KN, Beddoe T, Tye-Din JA, Mannering SI, Purcell AW, McCluskey J, Anderson RP, Koning F, Reid HH, Rossjohn J, Immunity. 2012 Oct 19;37(4):611-21. doi: 10.1016/j.immuni.2012.07.013. Epub 2012 , Oct 11. PMID:23063329
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.