BACKGROUND: In coeliac disease (CD), the upper bowel lesion is associated with a marked infiltration of the mucosa with Th1 cells secreting interferon gamma (IFNgamma) and expressing the Th1-associated transcription factor, T-bet. However, the molecular mechanisms which regulate T-bet and promote the Th1 cell response are unknown. OBJECTIVE: To examine whether interleukin 21 (IL21), a cytokine that regulates T cell activation, has a role in CD. METHODS: Duodenal mucosal samples were taken from CD patients and normal controls. IL21 and T-bet were examined by real-time PCR and western blotting, and IFNgamma was assessed by real-time PCR and ELISA. The effect of blockade of endogenous IL21 on the expression of T-bet was examined in an ex vivo culture of biopsies taken from untreated CD patients. Finally, the role of IL21 in controlling T-bet and IFNgamma was also evaluated in cultures of biopsies taken from treated CD patients and cultured with a peptic-tryptic digest of gliadin (PT) in the presence or absence of a neutralising IL21 antibody. RESULTS: Enhanced IL21 RNA and protein expression was seen in duodenal samples from untreated CD patients. Blockade of IL21 activity in biopsies of untreated CD patients reduced T-bet and IFNgamma secretion. Stimulation of treated CD biopsies with PT enhanced IL21 expression, and neutralisation of IL21 largely prevented PT-driven T-bet and IFNgamma induction. CONCLUSIONS: IL21 is overproduced in the mucosa of CD patients, where it helps sustain T-bet expression and IFNgamma production.