Title: Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease
Authors: 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
Issue Year: 2012
Publisher CELL PRESS
Series IMMUNITY: 37(4): 611-621
Abstract 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 HLADQ8-alpha-I-gliadin, in which all complementarity-determining region-beta (CDR beta) loops interact with the gliadin peptide. Mutagenesis at the TRBV9*01-TCR-HLA-DQ8-alpha-I-gliadin interface provides an energetic basis for the V beta 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.
URI: https://publications.svi.edu.au/publications/1602
Other Identifiers 10.1016/j.immuni.2012.07.013
Publication type Article
Find it online http://www.cell.com/immunity/abstract/S1074-7613%2812%2900419-0