HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease.
Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, alpha-gliadin AJ133612 and gamma-gliadin M36999. For alpha-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For gamma-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some gamma-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.
Tollefsen
Stig
S
Institute of Immunology, University of Oslo, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
Arentz-Hansen
Helene
H
Fleckenstein
Burkhard
B
Molberg
Oyvind
O
Ráki
Melinda
M
Kwok
William W
WW
Jung
Günther
G
Lundin
Knut E A
KE
Sollid
Ludvig M
LM
D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D019281:Dimerization; D000939:Epitopes / Q000737:chemistry; D005903:Gliadin / Q000737:chemistry / Q000235:genetics; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D018928:Immunity, Mucosal; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D006680:HLA Antigens; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D010446:Peptide Fragments; D005903:Gliadin