HLA-DQ2-restricted gluten-reactive T cells produce IL-21 but not IL-17 or IL-22

We have analyzed the production of the effector cytokines interleukin (IL)-17, IL-21, and IL-22 in gluten-reactive CD4(+) T cells of celiac disease patients, either cultured from small intestinal biopsies or isolated from peripheral blood after an oral gluten challenge. Combining intracellular cytokine staining with DQ2-alpha-II gliadin peptide tetramer staining of intestinal polyclonal T-cell lines, we found that gluten-specific T cells produced interferon-gamma (IFN-gamma) and IL-21, but not IL-17 or IL-22, even if other T cells of the same lines produced these cytokines. Similarly, in DQ2-alpha-II-specific T cells in peripheral blood of gluten-challenged patients, very few stained for intracellular IL-17, whereas many cells stained for IFN-gamma. We conclude that gluten-reactive T cells produce IL-21 and IFN-gamma, but not IL-17. Their production of IL-21 suggests a role for this cytokine in the pathogenesis of celiac disease.