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

Jan Petersen, Veronica Montserrat, Jorge R Mujico, Khai Lee Loh, Dennis Beringer, Mennno van Lummel, Allan Thompson, M Luisa Mearin, Joachim Schweizer, Yvonne Kooy-Winkelaar, Jeroen van Bergen, Jan W Drijfhout, Wan-Ting Kan, Nicole L La Gruta, Robert P Anderson, Hugh Harrington Reid, Frits Koning, Jamie Rossjohn

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111 Citations (Scopus)

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-alpha1a and DQ2.5-glia-alpha2. We determined the ternary structures of four distinct biased TCRs specific for those epitopes. All three TCRs specific for DQ2.5-glia-alpha2 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 CDR3beta loop acted as the lynchpin within this common docking footprint. Although the TCRs specific for DQ2.5-glia-alpha1a and DQ2.5-glia-alpha2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
Original languageEnglish
Pages (from-to)480 - 490
Number of pages11
JournalNature Structural & Molecular Biology
Volume21
Issue number5
DOIs
Publication statusPublished - 2014

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