Smad4 deficiency in T cells leads to the Th17-associated development of premalignant gastroduodenal lesions in mice

While there is evidence that specific T cell populations can promote the growth of established tumors, instances where T cell activity causes neoplasms to arise de novo are infrequent. Here, we employed two conditional mutagenesis systems to delete the TGF-beta signaling pathway component Smad4 in T cells and observed the spontaneous development of massive polyps within the gastroduodenal regions of mice. The epithelial lesions contained increased levels of transcripts encoding IL-11, IL-6, TGF-beta, IL-1 beta, and TNF-alpha, and lamina propria cells isolated from lesions contained abundant IL-17A(+)CD4(+) T cells. Furthermore, we found that Smad4 deficiency attenuated TGF-beta-mediated in vitro polarization of FoxP3(+)CD4(+) T cells, but not IL-17A(+)CD4(+) T cells, suggesting that the epithelial lesions may have arisen as a consequence of unchecked Th17 cell activity. Proinflammatory cytokine production likely accounted for the raised levels of IL-11, a cytokine known to promote gastric epithelial cell survival and hyperplasia. Consistent with IL-11 having a pathogenic role in this model, we found evidence of Stat3 activation in the gastric polyps. Thus, our data indicate that a chronic increase in gut Th17 cell activity can be associated with the development of premalignant lesions of the gastroduodenal region.