Increased production of interleukin-21, but not interleukin-17A, in the small intestine characterizes pediatric celiac disease

Celiac disease (CD) is caused by inflammatory CD4 + T-cell responses to dietary gluten. It is unclear whether interleukin (IL)-21 and IL-17A contribute to CD onset and lesion severity; therefore, we investigated IL-21 and IL-17A expression in biopsies from pediatric CD patients with different histopathological scores. High numbers of IL-21-producing cells were observed in pediatric CD lesions, even Marsh 1-2 lesions, whereas increased numbers of IL-17 secreting cells were not observed. Intraepithelial lymphocytes, CD4 + T cells and also neutrophils secreted IL-21. Flow cytometry of lamina propria cells revealed a large population of IL-21- and interferon-γ (IFN-γ)-secreting CD3 + T cells that did not secrete IL-17A. Adult CD patient biopsies also contained high numbers of IL-21-positive cells; however, enhanced numbers of IL-17-positive cells were observed in a small subgroup of patients with severe lesions. As duodenal tissue damage increases contact with microbe-associated molecular patterns, we hypothesized that microbial sensing by Toll-like receptors (TLRs) modulates T cell-derived cytokine secretion. Costimulation with TLR3 ligands during polyclonal T-cell activation significantly increased IL-21 secretion, whereas TLR2 ligands selectively enhanced IL-17A. These results demonstrate that an IL-17A-independent increase in IL-21 production by CD4 + T cells is characteristic of pediatric CD. We hypothesize that incidental IL-17 secretion is caused by tissue damage rather than gluten-specific responses.