Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease
Details
Publication Year 2012-10-19, Volume 37, Issue #4, Page 611-621
Journal Title
IMMUNITY
Publication Type
Journal Article
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.
Publisher
CELL PRESS
Keywords
MAJOR HISTOCOMPATIBILITY COMPLEX; TISSUE TRANSGLUTAMINASE; STRUCTURAL BASIS; IMMUNE-RESPONSES; CEREAL TOXICITY; SPECIFICITY; RECOGNITION; EPITOPES; TCR; DEAMIDATION
WEHI Research Division(s)
Immunology
Rights Notice
Copyright © 2012 Elsevier Inc. All rights reserved.


Creation Date: 2012-10-19 12:00:00
Last Modified: 0001-01-01 12:00:00
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