Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 21, Issue 5, Pages 480-488Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2817
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Funding
- Australian Research Council
- National Health and Medical Research Council (NHMRC) of Australia
- Dutch government [BSIK03009]
- NHMRC
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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-alpha 1a and DQ2.5-glia-alpha 2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5glia-alpha 2 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 CDR3 beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha 1a a and DQ2.5-glia-alpha 2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
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