HLA binding and T cell recognition of a tissue transglutaminase-modified gliadin epitope

DQ2 confers susceptibility to celiac disease (CD) and intestinal CD4(+) T c ells of DQ2(+) CD patients preferentially recognize deamidated gliadin pept ides. This modification can be mediated by tissue transglutaminase (tTG). W e have investigated what role the tTG-modified residues play in DQ2 binding and T cell presentation using a model gamma-gliadin peptide (residues 134- 153). Treatment of this peptide with tTG resulted in deamidation of Gin res idues at positions 140, 148 and 150. Two of these residues act as DQ2 ancho rs at position P7 (148) and P9 (150) and increased the affinity of the modi fied peptide for DQ2 50-fold. Testing of a mutant DQ2 molecule demonstrated that the Lys residue at beta 71 of DQ2 is important for binding of the dea midated peptide. A variant DQ2 molecule (with the same beta-chain but diffe rent alpha-chain) that does not confer susceptibility to GD was capable of presenting the gliadin peptide, but not pepsin/trypsin-digested gliadin, eq ually well to a T cell. This suggests that processing events might be invol ved in the preferential presentation of the gliadin peptide by the DQ2 mole cule. Substitution of Gln with Glu in some positions not targeted by tTG, b ut in positions likely to be deamidated via non-enzymatic mechanisms, disru pted T cell recognition;This provides additional evidence that tTG is respo nsible for modification of gliadin in vivo.