T-cell recognition of HLA-DQ2-bound gluten peptides can be influenced by an N-terminal proline at p-1.
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 gamma-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.
Stepniak
Dariusz
D
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, P.O. BOX 9600, 2300 RC, Leiden, The Netherlands.
Vader
L Willemijn
LW
Kooy
Yvonne
Y
van Veelen
Peter A
PA
Moustakas
Antonis
A
Papandreou
Nikolaos A
NA
Eliopoulos
Elias
E
Drijfhout
Jan Wouter
JW
Papadopoulos
George K
GK
Koning
Frits
F
D000595:Amino Acid Sequence; D003198:Computer Simulation; D030562:Databases, Protein; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005983:Glutens / Q000737:chemistry / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011392:Proline / Q000737:chemistry*; D013601:T-Lymphocytes / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D010446:Peptide Fragments; D005983:Glutens; D011392:Proline