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*0201.

CD is precipitated in susceptible individuals by ingestion of wheat gluten. The disease is strongly associated to the HLA-DQ(alpha 1*0501, beta 1*0201) (DQ2) heterodimer, where both the DQ alpha and DQ beta chains are required for susceptibility. We have recently shown that gluten-specific CD4+ T cells from the small intestinal mucosa of CD patients are predominantly restricted by the CD-associated HLA-DQ(alpha 1*0501, beta 1*0201) heterodimer. Here we report studies on the influence of aa substitutions in the DQ beta 1*0201 chain on DQ2-restricted T-cell recognition of gluten antigens. A B-LCL expressing the DQ(alpha 1*501, beta 1*0301) heterodimer was transfected with the DQB1*0201 gene, or with DQB1*0201 genes altered by site-directed mutagenesis. Surface expression of the wild-type or mutated DQ(alpha 1*0501, beta 1*0201) heterodimers was observed in the transfectants. Seven DQ2-restricted, gluten-specific TCCs were then investigated with respect to their ability to recognize antigen presented by the transfectants. All TCCs were sensitive to one or more of the aa substitutions induced but showed different response patterns. The results demonstrate that single aa substitutions of the DQ beta 1*0201 chain at positions in the peptide-binding cleft of DQ(alpha 1*0501, beta 1*0201) may affect binding of gluten-derived peptides and/or interfere with T-cell recognition. Because all seven TCCs studied were differently affected, they probably differ with respect to glutenpeptide and/or DQ(alpha 1*0501, beta 1*0201) restriction fine specificity.