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

Jan Petersen, Yvonne Kooy-Winkelaar, Khai Lee Loh, Mai Tran, Jeroen van Bergen, Frits Koning, Jamie Rossjohn, Hugh H. Reid

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1643-1657
Number of pages15
JournalStructure
Volume24
Issue number10
DOIs
Publication statusPublished - 4 Oct 2016

Cite this

Petersen, Jan ; Kooy-Winkelaar, Yvonne ; Loh, Khai Lee ; Tran, Mai ; van Bergen, Jeroen ; Koning, Frits ; Rossjohn, Jamie ; Reid, Hugh H. / Diverse T Cell receptor gene usage in HLA-DQ8-associated celiac disease converges into a consensus binding solution. In: Structure. 2016 ; Vol. 24, No. 10. pp. 1643-1657.
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abstract = "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.",
author = "Jan Petersen and Yvonne Kooy-Winkelaar and Loh, {Khai Lee} and Mai Tran and {van Bergen}, Jeroen and Frits Koning and Jamie Rossjohn and Reid, {Hugh H.}",
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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; Reid, Hugh H.

In: Structure, Vol. 24, No. 10, 04.10.2016, p. 1643-1657.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Diverse T Cell receptor gene usage in HLA-DQ8-associated celiac disease converges into a consensus binding solution

AU - Petersen, Jan

AU - Kooy-Winkelaar, Yvonne

AU - Loh, Khai Lee

AU - Tran, Mai

AU - van Bergen, Jeroen

AU - Koning, Frits

AU - Rossjohn, Jamie

AU - Reid, Hugh H.

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AB - 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.

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DO - 10.1016/j.str.2016.07.010

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