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© The Rockefeller University Press, 0022-1007/2000/2/603/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 4, February 21, 2000 603-612

Original Article

The Intestinal T Cell Response to {alpha}-Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

Helene Arentz-Hansena, Roman Körnerb, Øyvind Molberga, Hanne Quarstena, Willemijn Vaderd, Yvonne M.C. Kooyd, Knut E.A. Lundina,c, Frits Koningd, Peter Roepstorffb, Ludvig M. Sollida, and Stephen N. McAdama

a From the Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway
b Department of Molecular Biology, Odense University, DK-5230 Odense M, Denmark
c Department of Gastroenterology, Ullevaal Hospital, 0407 Oslo, Norway
d Department of Immunohaematology and Blood Bank, Leiden University Hospital, 2300 RC Leiden, The Netherlands
Institute of Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.47-22-20-36-9347-22-86-85-52

stephenm{at}labmed.uio.no

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.

Key Words: HLA-DQ2 • modification • gluten • oral tolerance • mucosal immunity

Abbreviations used in this paper: CD, celiac disease; TCC, T cell clone; TCL, T cell line; tTG, tissue transglutaminase.

© 2000 The Rockefeller University Press


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