Immunogenetics

, Volume 57, Issue 1–2, pp 8–15 | Cite as

T-cell recognition of HLA-DQ2-bound gluten peptides can be influenced by an N-terminal proline at p-1

  • Dariusz Stepniak
  • L. Willemijn Vader
  • Yvonne Kooy
  • Peter A. van Veelen
  • Antonis Moustakas
  • Nikolaos A. Papandreou
  • Elias Eliopoulos
  • Jan Wouter Drijfhout
  • George K. Papadopoulos
  • Frits Koning
Original Paper

Abstract

Recent research has implicated a large number of gluten-derived peptides in the pathogenesis of celiac disease, a preponderantly HLA-DQ2-associated disorder. Current evidence indicates that the core of some of those peptides is ten amino acids long, while HLA class II normally accommodates nine amino acids in the binding groove. We have now investigated this in detail, using gluten-specific T-cell clones, HLA-DQ2-specific peptide-binding assays and molecular modelling. T-cell recognition of both a γ-gliadin peptide and a low-molecular-weight glutenin peptide was found to be strictly dependent on a ten-amino acids-long peptide. Subsequent peptide-binding studies indicated that the glutenin peptide bound in a conventional p1/p9 register, with an additional proline at p-1. Testing of substitution analogues demonstrated that the nature of the amino acid at p-1 strongly influenced T-cell recognition of the peptide. Moreover, molecular modelling confirmed that the glutenin peptide binds in a p1/p9 register, and that the proline at p-1 points upward towards the T-cell receptor. Database searches indicate that a large number of potential T-cell stimulatory gluten peptides with an additional proline at relative position p-1 exist, suggesting that the recognition of other gluten peptides may depend on this proline as well. This knowledge may be of importance for the identification of additional T-cell stimulatory gluten peptides and the design of a peptide-based, tolerance-inducing therapy.

Keywords

Celiac disease Gluten epitope HLA-DQ2 

Notes

Acknowledgements

This study was supported by the Dutch Organization for Scientific Research (ZonMw grant 912-02-028), a grant from the EU (BHM4-CT98-3087), the ‘Stimuleringsfonds Voedingsonderzoek LUMC’ and the Centre for Medical Systems Biology (CMSB), a center of excellence approved by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NWO). G.K.P. was supported by grants from the Technological Educational Institute of Epirus Research Committee, and from the European Union’s 3rd Framework Program for Regional Development (Program EPEAEK, Scheme ‘Archimedes’). We wish to thank Dr. C.Y. Kim for kindly providing the coordinates of the HLA-DQ2 complex and Mr. Demetrios Kyrkas for technical support. We thank Dr. Tom Ottenhoff for critical reading of the manuscript.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Dariusz Stepniak
    • 1
  • L. Willemijn Vader
    • 1
  • Yvonne Kooy
    • 1
  • Peter A. van Veelen
    • 2
  • Antonis Moustakas
    • 3
  • Nikolaos A. Papandreou
    • 4
  • Elias Eliopoulos
    • 4
  • Jan Wouter Drijfhout
    • 1
  • George K. Papadopoulos
    • 3
  • Frits Koning
    • 1
  1. 1.Department of Immunohematology and Blood TransfusionLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Centre for Medical Systems BiologyLeidenThe Netherlands
  3. 3.Laboratory of Biochemistry and Biophysics, Faculty of Agricultural TechnologyTechnological Educational Institute of EpirusArtaGreece
  4. 4.Laboratory of Genetics, Department of Agricultural BiotechnologyAgricultural University of AthensAthensGreece

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