title: Determinants of gliadin-specific T cell selection in celiac disease.
abstract: In HLA-DQ8-associated celiac disease (CD), the pathogenic T cell response is directed toward an immunodominant α-gliadin-derived peptide (DQ8-glia-α1). However, our knowledge of TCR gene usage within the primary intestinal tissue of HLA-DQ8 (+) CD patients is limited. We identified two populations of HLA-DQ8-glia-α1 tetramer(+) CD4(+) T cells that were essentially undetectable in biopsy samples from patients on a gluten-free diet but expanded rapidly and specifically after antigenic stimulation. Distinguished by expression of TRBV9, both T cell populations displayed biased clonotypic repertoires and reacted similarly against HLA-DQ8-glia-α1. In particular, TRBV9 paired most often with TRAV26-2, whereas the majority of TRBV9(-) TCRs used TRBV6-1 with no clear TRAV gene preference. Strikingly, both tetramer(+)/TRBV9(+) and tetramer(+)/TRBV9(-) T cells possessed a non-germline-encoded arginine residue in their CDR3α and CDR3β loops, respectively. Comparison of the crystal structures of three TRBV9(+) TCRs and a TRBV9(-) TCR revealed that, as a result of distinct TCR docking modes, the HLA-DQ8-glia-α1 contacts mediated by the CDR3-encoded arginine were almost identical between TRBV9(+) and TRBV9(-) TCRs. In all cases, this interaction centered on two hydrogen bonds with a specific serine residue in the bound peptide. Replacement of serine with alanine at this position abrogated TRBV9(+) and TRBV9(-) clonal T cell proliferation in response to HLA-DQ8-glia-α1. Gluten-specific memory CD4(+) T cells with structurally and functionally conserved TCRs therefore predominate in the disease-affected tissue of patients with HLA-DQ8-mediated CD.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Jan
authors.initials: J
authors.lastname: Petersen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands;
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Bergen
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Khai Lee
authors.initials: KL
authors.lastname: Loh
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands;
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kooy-Winkelaar
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Dennis X
authors.initials: DX
authors.lastname: Beringer
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands;
authors.forename: Allan
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Department of Gastroenterology, Free University Medical Center, Amsterdam 1081 HZ, the Netherlands;
authors.forename: Sjoerd F
authors.initials: SF
authors.lastname: Bakker
authors.affiliation: Department of Gastroenterology, Free University Medical Center, Amsterdam 1081 HZ, the Netherlands;
authors.forename: Chris J J
authors.initials: CJ
authors.lastname: Mulder
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; and.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; and.
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; and Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; and jamie.rossjohn@monash.edu hugh.reid@monash.edu F.Koning@lumc.nl.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; jamie.rossjohn@monash.edu hugh.reid@monash.edu F.Koning@lumc.nl.
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; jamie.rossjohn@monash.edu hugh.reid@monash.edu F.Koning@lumc.nl.
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
mesh_terms: D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D060966:Clonal Selection, Antigen-Mediated / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005903:Gliadin / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; D000949:Histocompatibility Antigens Class II; D046912:Multiprotein Complexes; D011948:Receptors, Antigen, T-Cell; D005903:Gliadin