HLA-DQ2-RESTRICTED T-CELL RECOGNITION OF GLUTEN-DERIVED PEPTIDES IN CELIAC-DISEASE - INFLUENCE OF AMINO-ACID SUBSTITUTIONS IN THE MEMBRANE DISTAL DOMAIN OF DQ-BETA-1(ASTERISK)0201

CD is precipitated in susceptible individuals by ingestion of wheat gl uten. The disease is strongly associated to the HLA-DQ(alpha 1X0501, beta 10201) (DQ2) heterodimer, where both the DQ alpha and DQ beta ch ains are required for susceptibility. We have recently shown that glut en-specific CD4(+) T cells from the small intestinal mucosa of CD pati ents are predominantly restricted by the CD-associated HLA-DQ(alpha 1 0501, beta 10201) heterodimer. Here we report studies on the influenc e of aa substitutions in the DQ beta 10201 chain on-DQ2-restricted T- cell recognition of gluten antigens. A B-LCL expressing the DQ(alpha 1 0501, beta 1*0301) heterodimer was transfected with the DQB1*0201 gen e, or with DQB 10201 genes altered by site-directed mutagenesis. Surf ace expression of the wild-type or mutated DQ(alpha 10501, beta*0201) heterodimers was observed in the transfectants. Seven DQ2-restricted, gluten-specific TCCs were then investigated with respect to their abi lity to recognize antigen presented by the transfectants. All TCCs wer e sensitive to one or more of the aa substitutions induced but showed different response patterns. The results demonstrate that single aa su bstitutions of the DQ beta 10201 chain at positions in the peptide-bi nding cleft of DQ(alpha 10501, beta 1*0201) may affect binding of glu ten-derived peptides and/or interfere with T-cell recognition. Because all seven TCCs studied were differently affected, they probably diffe r with respect to gluten peptide and/or DQ(alpha 10501, beta 1*0201) restriction fine specificity.