title: The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk.
abstract: Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in the majority of individuals. We report here that the C57BL/6 mouse model of experimental infection with the closely related Helicobacter felis recapitulates this wide range in host susceptibility. Although the majority of infected animals develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia, and intestinal metaplasia, a subset of mice is completely protected from preneoplasia. Protection is associated with a failure to mount an IFN-gamma response to the infection and with a concomitant high Helicobacter burden. Using a vaccine model as well as primary infection and adoptive transfer models, we demonstrate that IFN-gamma, secreted predominantly by CD4(+)CD25(-) effector T(H) cells, is essential for Helicobacter clearance, but at the same time mediates the formation of preneoplastic lesions. We further provide evidence that IFN-gamma triggers a common transcriptional program in murine gastric epithelial cells in vitro and in vivo and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-gamma in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population.
authors.affiliation: Institute of Molecular Cancer Research and.
authors.forename: Ayca
authors.initials: A
authors.lastname: Sayi
authors.forename: Esther
authors.initials: E
authors.lastname: Kohler
authors.forename: Iris
authors.initials: I
authors.lastname: Hitzler
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnold
authors.forename: Reto
authors.initials: R
authors.lastname: Schwendener
authors.forename: Hubert
authors.initials: H
authors.lastname: Rehrauer
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D012306:Risk; D013274:Stomach Neoplasms / Q000209:etiology* / Q000382:microbiology; D014158:Transcription, Genetic; D014611:Vaccination
chemical_list: D007371:Interferon-gamma