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

• Published in: The Journal of clinical investigation 2011-10, Vol.121 (10), p.4030-4042
• Main Authors: Hahn, Jennifer Nancy, Falck, Vincent George, Jirik, Frank Robert
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Biomedical research; Cytokines; Development and progression; Disease Models, Animal; Gastrointestinal Neoplasms - etiology; Gastrointestinal Neoplasms - immunology; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Gene Expression; Interleukin-11; Interleukin-11 - genetics; Interleukin-1beta - genetics; Interleukin-6 - genetics; Intestinal Polyps - etiology; Intestinal Polyps - immunology; Intestinal Polyps - metabolism; Intestinal Polyps - pathology; Kinases; Lymphocytes; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Mutant Strains; Mice, Transgenic; Pathogenesis; Physiological aspects; Polyps; Precancerous Conditions - etiology; Precancerous Conditions - immunology; Precancerous Conditions - metabolism; Precancerous Conditions - pathology; Smad4 Protein - deficiency; Smad4 Protein - genetics; T cell receptors; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; Th17 Cells - immunology; Th17 Cells - metabolism; Th17 Cells - pathology; Transforming Growth Factor beta - genetics; Transforming growth factors; Tumor Necrosis Factor-alpha - genetics; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI45114

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-β 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-β, IL-1β, and TNF-α, and lamina propria cells isolated from lesions contained abundant IL-17A+CD4+ T cells. Furthermore, we found that Smad4 deficiency attenuated TGF-β-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.