title: Spontaneous Intestinal Tumorigenesis in Apc (/Min+) Mice Requires Altered T Cell Development with IL-17A.
abstract: The control of inflammatory diseases requires functional regulatory T cells (Tregs) with significant Gata-3 expression. Here we address the inhibitory role of Tregs on intestinal tumorigenesis in the Apc (/Min+) mouse model that resembles human familial adenomatous polyposis (FAP). Apc (/Min+) mice had a markedly increased frequency of Foxp3+ Tregs and yet decreased Gata-3 expression in the lamina propria. To address the role of heterozygous Apc gene mutation in Tregs, we generated Foxp3-Cre, Apc (flox/+) mice. Tregs from these mice effectively inhibited tumorigenesis comparable to wild type Tregs after adoptive transfer into Apc (/Min+) mice, demonstrating that the heterozygous Apc gene mutation in Tregs does not induce the loss of control over tumor microenvironment. Adoptive transfer of in vitro generated Apc (/Min+) iTregs (inducible Tregs) failed to inhibit intestinal tumorigenesis, suggesting that naïve CD4 T cells generated from Apc (/Min+) mice thymus were impaired. We also showed that adoptively transferred IL-17A-deficient Apc (/Min+) Tregs inhibited tumor growth, suggesting that IL-17A was critical to impair the tumor regression function of Apc (/Min+) Tregs. Taken together, our results suggest that both T cell development in a functional thymus and IL-17A control the ability of Treg to inhibit intestinal tumorigenesis in Apc (/Min+) mice.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Wook-Jin
authors.initials: WJ
authors.lastname: Chae
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000276:immunology / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000276:immunology*; D004195:Disease Models, Animal; D006579:Heterozygote; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D020381:Interleukin-17