Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease

Background & Aims: The chronic, small intestinal inflammation that defines celiac disease is initiated by a HLA-DQ2 restricted T-cell response to ingested gluten peptides after their in vivo deamidation by tissue transglutaminase (TG2). To date, celiac disease can only be treated by a lifelong abstinence from foods that contain wheat, rye, or barley; better therapeutic options are hence needed. An attractive target would be to identify nontoxic wheat cultivars or components thereof with intact baking qualities. Because these qualities are mainly determined by the high molecular weight (HMW) glutenin proteins of gluten, it is critical to know if these proteins are toxic or, more specifically, if they will trigger the activation of T cells in the celiac lesion. Methods: Different, highly purified HMW glutenins were isolated from wheat cultivars or expressed as recombinant proteins. The proteins were first tested for recognition by a large panel of gluten-specific T-cell lines established from celiac lesions and then applied during ex vivo challenges of celiac biopsies to allow for a direct identification of HMW specific T cells. Results: Intestinal T-cell responses to TG2-deamidated HMW glutenins but not the corresponding native proteins were detectable in 9 of the 22 adult and childhood celiac disease patients tested. Conclusions: T cells within celiac lesions frequently recognize deamidated HMW glutenin proteins. This finding questions the possibility of implementing these proteins in novel food items destined to be nontoxic for celiac disease patients.