The intestinal T cell response to alpha-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase.
The great majority of patients that are intolerant of wheat gluten protein due to celiac disease (CD) are human histocompatibility leukocyte antigen (HLA)-DQ2(+), and the remaining few normally express HLA-DQ8. These two class II molecules are chiefly responsible for the presentation of gluten peptides to the gluten-specific T cells that are found only in the gut of CD patients but not of controls. Interestingly, tissue transglutaminase (tTG)-mediated deamidation of gliadin plays an important role in recognition of this food antigen by intestinal T cells. Here we have used recombinant antigens to demonstrate that the intestinal T cell response to alpha-gliadin in adult CD is focused on two immunodominant, DQ2-restricted peptides that overlap by a seven-residue fragment of gliadin. We show that tTG converts a glutamine residue within this fragment into glutamic acid and that this process is critical for T cell recognition. Gluten-specific T cell lines from 16 different adult patients all responded to one or both of these deamidated peptides, indicating that these epitopes are highly relevant to disease pathology. Binding studies showed that the deamidated peptides displayed an increased affinity for DQ2, a molecule known to preferentially bind peptides containing negatively charged residues. Interestingly, the modified glutamine is accommodated in different pockets of DQ2 for the different epitopes. These results suggest modifications of anchor residues that lead to an improved affinity for major histocompatibility complex (MHC), and altered conformation of the peptide-MHC complex may be a critical factor leading to T cell responses to gliadin and the oral intolerance of gluten found in CD.
Arentz-Hansen
H
H
Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.
Körner
R
R
Molberg
O
O
Quarsten
H
H
Vader
W
W
Kooy
Y M
YM
Lundin
K E
KE
Koning
F
F
Roepstorff
P
P
Sollid
L M
LM
McAdam
S N
SN
D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites; D002446:Celiac Disease / Q000276:immunology*; D002460:Cell Line; D002648:Child; D016384:Consensus Sequence; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005903:Gliadin / Q000737:chemistry / Q000494:pharmacology*; D005973:Glutamine; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D007413:Intestinal Mucosa / Q000276:immunology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D011503:Transglutaminases / Q000378:metabolism*
D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005973:Glutamine; D005903:Gliadin; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins