학술논문
T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease.
Document Type
Article
Author
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; Rossjohn, Jamie
Source
Subject
*T cells
*CELIAC disease
*GLIADINS
*MUTAGENESIS
*AFFINITY (Canon law)
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Language
ISSN
1545-9993
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. [ABSTRACT FROM AUTHOR]