The intestinal T cell response to alpha-gliadin in adult celiac disease isfocused 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 clas s II molecules are chiefly responsible for the presentation of gluten pepti des to the gluten-specific T cells that are found only in the gut of CD pat ients but not of controls. Interestingly, tissue transglutaminase (tTG)-med iated 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 ol-gliadin in adult CD is focused on two immunodominant, DQ2-restricted peptides that overlap b y a seven-residue fragment of gliadin. We show that tTG converts a glutamin e residue within this fragment into glutamic acid and that this process is critical for T cell recognition. Gluten-specific T cell lines from 16 diffe rent adult patients all responded to one or both of these deamidated peptid es, indicating that these epitopes are highly relevant to disease pathology . Binding studies showed that the deamidated peptides displayed an increase d affinity for DQ2, a molecule known to preferentially bind peptides contai ning 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 conformati on of the peptide-MHC complex may be a critical factor leading to T cell re sponses to gliadin and the oral intolerance of gluten found in CD.