Conclusions
AIE is characterized by the appearance of unconventional IL-17-producing IELs, which could be generated locally by pro-inflammatory cytokines and TGF-β. These results suggest that Foxp3(+)Tregs and Treg-derived TGF-β regulate IL-17 production by IELs in the small intestine and in AIE.
Methods
Duodenal biopsies from a patient with AIE at baseline and following drug-induced remission were analyzed by immunohistochemistry, immunofluorescence, and flow cytometry, and
Results
The quantitative deficit of Foxp3 expression in Tregs in AIE associates with unrestrained IL-17 production by IELs. Interleukin (IL)-17-producing IELs were rare in the uninflamed duodenum and in the ileum of Crohn's disease patients, and disappeared upon drug-induced AIE remission. IL-17 upregulation in CD4(+)IELs and CD4(+)LP T cells had different requirements for pro-inflammatory cytokines. Moreover, transforming growth factor-β (TGF-β) selectively enhanced IL-17 production by CD8(+)IELs. Intriguingly, although Foxp3(low)Tregs in AIE were poorly suppressive, they could upregulate GARP-LAP/TGF-β surface expression and enhanced IL-17 production selectively by CD8(+)IELs. Finally, phosphorylated Smad2/3 was detectable in duodenal CD8(+) lymphocytes in active AIE in situ, indicating that they received signals from the TGF-β receptor in vivo. Conclusions: AIE is characterized by the appearance of unconventional IL-17-producing IELs, which could be generated locally by pro-inflammatory cytokines and TGF-β. These results suggest that Foxp3(+)Tregs and Treg-derived TGF-β regulate IL-17 production by IELs in the small intestine and in AIE.