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

doi:10.1016/j.str.2016.07.010

Diverse T Cell Receptor Gene Usage in HLA-DQ8-Associated Celiac Disease Converges into a Consensus Binding Solution

Structure. 2016 Oct 4;24(10):1643-1657. doi: 10.1016/j.str.2016.07.010. Epub 2016 Aug 25.

Authors

Jan Petersen¹, Yvonne Kooy-Winkelaar², Khai Lee Loh¹, Mai Tran¹, Jeroen van Bergen², Frits Koning³, Jamie Rossjohn⁴, Hugh H Reid⁵

Affiliations

¹ Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
² Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
³ Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. Electronic address: [email protected].
⁴ Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: [email protected].
⁵ Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia. Electronic address: [email protected].

PMID: 27568928
DOI: 10.1016/j.str.2016.07.010

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigen Presentation
Celiac Disease / immunology*
Cells, Cultured
Gliadin / immunology*
HLA-DQ Antigens / chemistry
HLA-DQ Antigens / genetics
HLA-DQ Antigens / metabolism*
Humans
Immunodominant Epitopes
Receptors, Antigen, T-Cell / chemistry
Receptors, Antigen, T-Cell / genetics*
Receptors, Antigen, T-Cell / metabolism
T-Lymphocytes / cytology
T-Lymphocytes / immunology

Substances

HLA-DQ Antigens
HLA-DQ8 antigen
Immunodominant Epitopes
Receptors, Antigen, T-Cell
Gliadin