Antigen presentation to celiac lesion-derived T cells of a 33-mer gliadin peptide naturally formed by gastrointestinal digestion.
Celiac disease is an HLA-DQ2-associated disorder characterized by intestinal T cell responses to ingested wheat gluten proteins. A peptide fragment of 33 residues (alpha(2)-gliadin 56-88) produced by normal gastrointestinal proteolysis contains six partly overlapping copies of three T cell epitopes and is a remarkably potent T cell stimulator after deamidation by tissue transglutaminase (TG2). This 33-mer is rich in proline residues and adopts the type II polyproline helical conformation in solution. In this study we report that after deamidation, the 33-mer bound with higher affinity to DQ2 compared with other monovalent peptides harboring gliadin epitopes. We found that the TG2-treated 33-mer was presented equally effectively by live and glutaraldehyde-fixed, EBV-transformed B cells. The TG2-treated 33-mer was also effectively presented by glutaraldehyde-fixed dendritic cells, albeit live dendritic cells were the most effective APCs. A strikingly increased T cell stimulatory potency of the 33-mer compared with a 12-mer peptide was also seen with fixed APCs. The 33-mer showed binding maximum to DQ2 at pH 6.3, higher than maxima found for other high affinity DQ2 binders. The 33-mer is thus a potent T cell stimulator that does not require further processing within APC for T cell presentation and that binds to DQ2 with a pH profile that promotes extracellular binding.
Qiao
Shuo-Wang
SW
Institute of Immunology, Rikshospitalet University Hospital, University of Oslo, Oslo, Norway. s.w.qiao@medisin.uio.no
Bergseng
Elin
E
Molberg
Øyvind
Ø
Xia
Jiang
J
Fleckenstein
Burkhard
B
Khosla
Chaitan
C
Sollid
Ludvig M
LM
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002446:Celiac Disease / Q000276:immunology* / Q000473:pathology; D002461:Cell Line, Transformed; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004063:Digestion; D000939:Epitopes / Q000276:immunology*; D005404:Fixatives / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D005903:Gliadin / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D005976:Glutaral / Q000494:pharmacology; D006683:HLA-DQ Antigens / Q000276:immunology*; D004854:Herpesvirus 4, Human; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D011503:Transglutaminases / Q000378:metabolism
D000939:Epitopes; D005404:Fixatives; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D010446:Peptide Fragments; D011994:Recombinant Proteins; C489632:alpha2-gliadin (56-88); D005903:Gliadin; D011392:Proline; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D005976:Glutaral