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Nat Struct Mol Biol. 2014 May;21(5):480-8. doi: 10.1038/nsmb.2817. Epub 2014 Apr 28.

T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease.

Author information

  • 11] Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. [2].
  • 21] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. [2].
  • 3Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
  • 4Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.
  • 5Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • 6Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
  • 7ImmusanT, Inc., Cambridge, Massachusetts, USA.
  • 81] Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. [2] [3].
  • 91] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. [2] [3].
  • 101] Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. [2] Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK. [3] Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. [4] [5].

Abstract

Celiac disease is a T cell-mediated disease induced by dietary gluten, a component of which is gliadin. 95% of individuals with celiac disease carry the HLA (human leukocyte antigen)-DQ2 locus. Here we determined the T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-α1a and DQ2.5-glia-α2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-α2 docked centrally above HLA-DQ2, which together with mutagenesis and affinity measurements provided a basis for the biased TCR usage. A non-germline encoded arginine residue within the CDR3β loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-α1a and DQ2.5-glia-α2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.

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PMID:
24777060
[PubMed - indexed for MEDLINE]
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