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Diverse T cell receptor gene usage in HLA-DQ8-associated celiac disease converges into a consensus binding solution

Petersen, Jan, Kooy-Winkelaar, Yvonne, Loh, Khai Lee, Tran, Mai, van Bergen, Jeroen, Koning, Frits, Rossjohn, Jamie and Reid, Hugh H. 2016. Diverse T cell receptor gene usage in HLA-DQ8-associated celiac disease converges into a consensus binding solution. Structure 24 (10) , pp. 1643-1657. 10.1016/j.str.2016.07.010

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In HLA-DQ8-associated celiac disease, TRAV26-2+-TRBV9+ and TRAV8-3+-TRBV6+ T cells recognize the immunodominant DQ8-glia-α1 epitope, whereupon a non-germline-encoded arginine residue played a key role in binding HLA-DQ8-glia-α1. Whether distinct T cell receptor (TCR) recognition modes exist for gliadin epitopes remains unclear. TCR repertoire analysis revealed populations of HLA-DQ8-glia-α1 and HLA-DQ8.5-glia-γ1 restricted TRAV20+-TRBV9+ T cells that did not possess a non-germline-encoded arginine residue. The crystal structures of a TRAV20+-TRBV9+ TCR-HLA-DQ8-glia-α1 complex and two TRAV20+-TRBV9+ TCR-HLA-DQ8.5-glia-γ1 complexes were determined. This revealed that the differential specificity toward DQ8-glia-α1 and DQ8.5-glia-γ1 was governed by CDR3β-loop-mediated interactions. Surprisingly, a germline-encoded arginine residue within the CDR1α 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Elsevier
ISSN: 0969-2126
Date of First Compliant Deposit: 27 July 2017
Date of Acceptance: 17 July 2016
Last Modified: 24 May 2018 22:47

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