T-cell Receptor Recognition of HLA-DQ2-gliadin Complexes Associated with Celiac Disease

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2014 Apr 30

PMID 24777060

Citations 86

Authors

Jan Petersen

Veronica Montserrat

Jorge R Mujico

Khai Lee Loh

Dennis X Beringer

Menno 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 H Reid

Frits Koning

Jamie Rossjohn

Affiliations

Soon will be listed here.

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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