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

Petersen, Jan, Montserrat, Veronica, Mujico, Jorge R., Loh, Khai Lee, Beringer, Dennis X., van Lummel, Menno, Thompson, Allan, Mearin, M Luisa, Schweizer, Joachim, Kooy-Winkelaar, Yvonne, van Bergen, Jeroen, Drijfhout, Jan W., Kan, Wan-Ting, La Gruta, Nicole L, Anderson, Robert P., Reid, Hugh H., Koning, Frits and Rossjohn, Jamie 2014. T-cell receptor recognition of HLA-DQ2–gliadin complexes associated with celiac disease. Nature Structural and Molecular Biology 21 (5) , pp. 480-488. 10.1038/nsmb.2817

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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-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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: immunology
Publisher: Nature Publishing Group
ISSN: 1545-9993
Date of Acceptance: 28 March 2014
Last Modified: 04 Jun 2017 09:07

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