Refining the rules of gliadin T cell epitope binding to the disease-associated DQ2 molecule in celiac disease: importance of proline spacing and glutamine deamidation.
Celiac disease is driven by intestinal T cells responsive to proline-rich gluten peptides that often harbor glutamate residues formed by tissue transglutaminase-mediated glutamine conversion. The disease is strongly associated with the HLA variant DQ2.5 (DQA1*05, DQB1*02), and intestinal gluten-reactive T cells from DQ2.5-positive patients are uniquely restricted by this HLA molecule. In this study, we describe the mapping of two novel T cell epitopes of gamma-gliadin and the experimental identification of the DQ2.5 binding register of these and three other gamma-gliadin epitopes. The new data extend the knowledge base for understanding the binding of gluten peptides to DQ2.5. The alignment of the experimentally determined binding registers of nine gluten epitopes reveal positioning of proline residues in positions P1, P3, P6, and P8 but never in positions P2, P4, P7, and P9. Glutamate residues formed by tissue transglutaminase-mediated deamidation are found in position P1, P4, P6, P7, or P9, but only deamidations in positions P4 and P6, and rarely in P7, seem to be crucial for T cell recognition. The majority of these nine epitopes are recognized by celiac lesion T cells when presented by the related but nonassociated DQ2.2 (DQA1*0201, DQB1*02) molecule. Interestingly, the DQ2.2 presentation for most epitopes is less efficient than presentation by the DQ2.5 molecule, and this is particularly prominent for the alpha-gliadin epitopes. Contrary to previous findings, our data do not show selective presentation of DQ2.5 over DQ2.2 for gluten epitopes that carry proline residues at the P3 position.
Institute of Immunology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway. s.w.qiao@labmed.uio.no
Shuo-Wang
SW
Qiao
Elin
E
Bergseng
Oyvind
O
Molberg
Günther
G
Jung
Burkhard
B
Fleckenstein
Ludvig M
LM
Sollid
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001665:Binding Sites; D002446:Celiac Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005903:Gliadin / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005973:Glutamine / Q000737:chemistry; D006683:HLA-DQ Antigens / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D005973:Glutamine; D005903:Gliadin; D011392:Proline