On the immune response to barley in celiac disease: Biased and public T‐cell receptor usage to a barley unique and immunodominant gluten epitope

Celiac disease (CeD) is driven by CD4+ T‐cell responses to dietary gluten proteins of wheat, barley, and rye when deamidated gluten epitopes are presented by certain disease‐associated HLA‐DQ allotypes. About 90% of the CeD patients express HLA‐DQ2.5. In such patients, five gluten epitopes dominate the anti‐gluten T‐cell response; two epitopes unique to wheat, two epitopes present in wheat, barley, and rye and one epitope unique to barley. Despite presence of barley in commonly consumed food and beverages and hence being a prominent source of gluten, knowledge about T‐cell responses elicited by barley in CeD is scarce. Therefore, in this study, we explored T‐cell response toward the barley unique epitope DQ2.5‐hor‐3 (PIPEQPQPY) by undertaking HLA‐DQ:gluten peptide tetramer staining, single‐cell T‐cell receptor (TCR) αβ sequencing, T‐cell cloning, and T‐cell proliferation studies. We demonstrate that majority of the CeD patients generate T‐cell response to DQ2.5‐hor‐3, and this response is characterized by clonal expansion, preferential TCR V‐gene usage and public TCR features thus echoing findings previously made for wheat gluten epitopes. The knowledge that biased and public TCRs underpin the T‐cell response to all the immunodominant gluten epitopes in CeD suggests that such T cells are promising diagnostic and therapeutic targets. By combining HLA‐DQ:gluten peptide tetramer staining and single cell TCR sequencing, we have shown that majority of the celiac disease patients generate T‐cell response to barley unique immunodominant gluten epitope (DQ2.5‐hor‐3) and the response is characterized by clonal expansion, preferential TCR V‐gene usage, and use of public TCRs.