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Diverse T Cell Receptor Gene Usage in HLA-DQ8-Associated Celiac Disease Converges into a Consensus Binding Solution

Jan Petersen1, Yvonne Kooy-Winkelaar2, Khai Lee Loh1

  • 1Infection and Immunity Program, The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.

Structure (London, England : 1993)
|August 30, 2016
PubMed

Insights

In celiac disease, T-cell receptors (TCRs) recognize HLA-DQ8-gliadin epitopes through convergent binding mechanisms. Structural analysis reveals germline-encoded residues can substitute for non-germline ones, driving TCR repertoire selection.

Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • Celiac disease involves an immune response to gliadin peptides presented by HLA-DQ8.
  • Previous studies identified specific T-cell receptors (TCRs) recognizing the DQ8-glia-α1 epitope, involving a non-germline-encoded arginine residue.

Purpose of the Study:

  • To investigate if distinct TCR recognition modes exist for different gliadin epitopes in HLA-DQ8-associated celiac disease.
  • To elucidate the structural basis of TCR specificity for gliadin epitopes.

Main Methods:

  • T-cell receptor repertoire analysis.
  • X-ray crystallography to determine the structures of TCR-HLA-gliadin complexes.

Main Results:

  • Identified TRAV20+-TRBV9+ T cells recognizing both HLA-DQ8-glia-α1 and HLA-DQ8.5-glia-γ1 without a non-germline arginine.
  • Crystal structures revealed CDR3β-loop interactions govern differential epitope specificity.
  • A germline-encoded arginine in the TRAV20+ TCR CDR1α loop substituted for the non-germline arginine in other TCRs.

Conclusions:

  • TCR repertoire selection in celiac disease is driven by a common mechanism favoring structural elements with convergent binding solutions for HLA-DQ8-gliadin recognition.
  • Both germline-encoded and non-germline-encoded residues contribute to TCR binding affinity and specificity in celiac disease.

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