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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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Acknowledgements

We thank the staff of the Monash crystallization facility and the Australian Synchrotron for assistance with crystallization and data collection, respectively. This work was supported by the Australian Research Council, the National Health and Medical Research Council (NHMRC) of Australia, the Celiac Disease Consortium and an Innovative Cluster approved by The Netherlands Genomics Initiative and was funded in part by the Dutch government (grant BSIK03009). We thank J. Tye-Din for assistance. J.R. is supported by an Australia Fellowship from the NHMRC.

Author information

Author notes

    • Jan Petersen
    •  & Veronica Montserrat

    These authors contributed equally to this work.

    • Hugh H Reid
    • , Frits Koning
    •  & Jamie Rossjohn

    These authors jointly directed this work.

Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia.

    • Jan Petersen
    • , Khai Lee Loh
    • , Dennis X Beringer
    • , Hugh H Reid
    •  & Jamie Rossjohn
  2. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.

    • Veronica Montserrat
    • , Jorge R Mujico
    • , Menno van Lummel
    • , Allan Thompson
    • , Yvonne Kooy-Winkelaar
    • , Jeroen van Bergen
    • , Jan W Drijfhout
    •  & Frits Koning
  3. Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands.

    • M Luisa Mearin
    •  & Joachim Schweizer
  4. Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.

    • Wan-Ting Kan
    •  & Nicole L La Gruta
  5. ImmusanT, Inc., Cambridge, Massachusetts, USA.

    • Robert P Anderson
  6. Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff, UK.

    • Jamie Rossjohn
  7. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.

    • Jamie Rossjohn

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Contributions

J.P. and V.M. are joint first authors. J.R.M., K.L.L., D.X.B., M.v.L., A.T., M.L.M., J.S., Y.K.-W., J.v.B., J.W.D., W.-T.K., N.L.L.G. and R.P.A. performed experiments, provided key reagents and/or analyzed data and/or provided intellectual input or helped write the manuscript. H.H.R., F.K. and J.R. are joint senior and corresponding authors, co-led the investigation and contributed to the design and interpretation of data, project management and writing of the manuscript.

Competing interests

R.P.A. is a co-inventor of patents pertaining to the use gluten peptides in therapeutics, diagnostics and nontoxic gluten. R.P.A. is a shareholder and Chief Scientific Officer of ImmusanT Inc., a company developing a peptide-based therapy and diagnostic suitable for celiac disease.

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https://doi.org/10.1038/nsmb.2817

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