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.
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References
Arentz-Hansen H, Korner R, Molberg O, Quarsten H, Vader W, Kooy YM, Lundin KE, Koning F, Roepstorff P, Sollid LM, McAdam SN (2000) The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase. J Exp Med 191:603–612
Arentz-Hansen H, McAdam SN, Molberg O, Fleckenstein B, Lundin KE, Jorgensen TJ, Jung G, Roepstorff P, Sollid LM (2002) Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues. Gastroenterology 123:803–809
Arnold PY, La Gruta NL, Miller T, Vignali KM, Adams PS, Woodland DL, Vignali DA (2002) The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues. J Immunol 169:739–749
De Oliveira DB, Harfouch-Hammoud E, Otto H, Papandreou NA, Stern LJ, Cohen H, Boehm BO, Bach J, Caillat-Zucman S, Walk T, Jung G, Eliopoulos E, Papadopoulos GK, van Endert PM (2000) Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition. Mol Immunol 37:813–825
Hennecke J, Wiley DC (2002) Structure of a complex of the human alpha/beta T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity. J Exp Med 195:571–581
Hennecke J, Carfi A, Wiley DC (2000) Structure of a covalently stabilized complex of a human alpha/beta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1. EMBO J 19:5611–5624
Jardetzky TS, Brown JH, Gorga JC, Stern LJ, Urban RG, Strominger JL, Wiley DC (1996) Crystallographic analysis of endogenous peptides associated with HLA-DR1 suggests a common, polyproline II-like conformation for bound peptides. Proc Natl Acad Sci USA 93:734–738
Kim CY, Quarsten H, Bergseng E, Khosla C, Sollid LM (2004) Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc Natl Acad Sci USA 101:4175–4179
Koelle DM, Johnson ML, Ekstrom AN, Byers P, Kwok WW (1997) Preferential presentation of herpes simplex virus T-cell antigen by HLA DQA1*0501/DQB1*0201 in comparison to HLA DQA1*0201/DQB1*0201. Hum Immunol 53:195–205
Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4:713–717
Molberg O, McAdam S, Lundin KE, Kristiansen C, Arentz-Hansen H, Kett K, Sollid LM (2001) T cells from celiac disease lesions recognize gliadin epitopes deamidated in situ by endogenous tissue transglutaminase. Eur J Immunol 31:1317–1323
Moudgil KD, Sercarz EE, Grewal IS (1998) Modulation of the immunogenicity of antigenic determinants by their flanking residues. Immunol Today 19:217–220
Reichstetter S, Papadopoulos GK, Moustakas AK, Swanson E, Liu AW, Beheray S, Ettinger RA, Nepom GT, Kwok WW (2002) Mutational analysis of critical residues determining antigen presentation and activation of HLA-DQ0602 restricted T-cell clones. Hum Immunol 63:185–193
Rudolph MG, Wilson IA (2002) The specificity of TCR/pMHC interaction. Curr Opin Immunol 14:52–65
Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E (1989) Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med 169:345–350
Vader LW, De Ru A, van der Wal Y, Kooy YM, Benckhuijsen W, Mearin ML, Drijfhout JW, van Veelen P, Koning F (2002a) Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med 195:643–649
Vader W, Kooy Y, van Veelen P, De Ru A, Harris D, Benckhuijsen W, Pena S, Mearin L, Drijfhout JW, Koning F (2002b) The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122:1729–37
Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, Spaenij L, Koning F (2003) The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci USA 100:12390–12395
Vartdal F, Johansen BH, Friede T, Thorpe CJ, Stevanovic S, Eriksen JE, Sletten K, Thorsby E, Rammensee HG, Sollid LM (1996) The peptide binding motif of the disease associated HLA-DQ (alpha 1*0501, beta 1*0201) molecule. Eur J Immunol 26:2764–2772
Wal Y van de, Kooy YMC, Drijfhout JW, Amons R, Koning F (1996) Peptide binding characteristics of the coeliac disease-associated DQ(alpha1*0501, beta1*0201) molecule. Immunogenetics 44:246–253
Wal Y van de, Kooy YM, Drijfhout JW, Amons R, Papadopoulos GK, Koning F (1997) Unique peptide binding characteristics of the disease-associated DQ(alpha 1*0501, beta 1*0201) vs the non-disease-associated DQ(alpha 1*0201, beta 1*0202) molecule. Immunogenetics 46:484–492
Wal Y van de , Kooy Y, van Veelen P, Pena S, Mearin L, Papadopoulos G, Koning F (1998a) Selective deamidation by tissue transglutaminase strongly enhances gliadin-specific T cell reactivity. J Immunol 161:1585–1588
Wal Y van de, Kooy YM, van Veelen PA, Pena SA, Mearin LM, Molberg O, Lundin KE, Sollid LM, Mutis T, Benckhuijsen WE, Drijfhout JW, Koning F (1998b) Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc Natl Acad Sci USA 95:10050–4
Wieser H, Seilmeier W, Belitz HD (1980) Comparative investigations of partial amino acid sequences of prolamines and glutelins from cereals. II. Fractionation of glutelins (Author’s translation). Z Lebensm Unters Forsch 171:430–436
Yassai M, Afsari A, Garlie J, Gorski J (2002) C-terminal anchoring of a peptide to class II MHC via the P10 residue is compatible with a peptide bulge. J Immunol 168:1281–1285
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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Stepniak, D., Vader, L.W., Kooy, Y. et al. T-cell recognition of HLA-DQ2-bound gluten peptides can be influenced by an N-terminal proline at p-1. Immunogenetics 57, 8–15 (2005). https://doi.org/10.1007/s00251-005-0780-8
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DOI: https://doi.org/10.1007/s00251-005-0780-8