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| Article Authors: | Sophie E Broughton; Jan Petersen; Alex Theodossis; Stephen W Scally; Khai Lee Loh; Allan Thompson; Jeroen van Bergen; Yvonne Kooy-Winkelaar; Kate N Henderson; Travis Beddoe; Jason A Tye-Din; Stuart I Mannering; Anthony W Purcell; James McCluskey; Robert P Anderson; Frits Koning; Hugh H Reid; Jamie Rossjohn |
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| Article Title: | Biased T Cell Receptor Usage Directed against Human Leukocyte Antigen DQ8-Restricted Gliadin Peptides Is Associated with Celiac Disease. |
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| Reference ID: | 1025186 |
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| 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-α-I-gliadin. The structure of a prototypical TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin complex shows that the TCR docks centrally above HLA-DQ8-α-I-gliadin, in which all complementarity-determining region-β (CDRβ) loops interact with the gliadin peptide. Mutagenesis at the TRBV9(∗)01-TCR-HLA-DQ8-α-I-gliadin interface provides an energetic basis for the Vβ 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. |
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| Affiliations: | The Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia. |
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| Date: | 2012 |
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| Reference Type: | Literature |
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| PubMed ID: | 23063329 |
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| Journal: | Immunity |
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| Journal Volume: | 37 |
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| Article Pages: | 611-21 |
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| Journal ISSN: | 1097-4180 |
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| Curation Last Updated: | 2013-01-28 20:01:32 |
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