title: Diverse T Cell Receptor Gene Usage in HLA-DQ8-Associated Celiac Disease Converges into a Consensus Binding Solution.
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.
authors: 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.
authors: Jan
authors: J
authors: Petersen
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
authors: Yvonne
authors: Y
authors: Kooy-Winkelaar
authors: 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.
authors: Khai Lee
authors: KL
authors: Loh
authors: 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.
authors: Mai
authors: M
authors: Tran
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.
authors: Jeroen
authors: J
authors: van Bergen
authors: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands. Electronic address: f.koning@lumc.nl.
authors: Frits
authors: F
authors: Koning
authors: 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: jamie.rossjohn@monash.edu.
authors: Jamie
authors: J
authors: Rossjohn
authors: 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: hugh.reid@monash.edu.
authors: Hugh H
authors: HH
authors: Reid
mesh_terms: D017951:Antigen Presentation; D002446:Celiac Disease / Q000276:immunology*; D002478:Cells, Cultured; D005903:Gliadin / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D005903:Gliadin