The CD4+ T cell-mediated IFN-γ response to Helicobacter infection is essential for clearance and determines gastric cancer risk

Ayca Sayi, Esther Kohler, Iris Hitzler, Isabelle Arnold, Reto Schwendener, Hubert Rehrauer, Anne Müller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

143 Citations (Scopus)

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-γresponse 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-γ, secreted predominantly by CD4+CD25- effector TH cells, is essential for Helicobacter clearance, but at the same time mediates the formation of preneoplastic lesions. We further provide evidence that IFN-γ 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-γ in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population.

Original languageEnglish
Pages (from-to)7085-7101
Number of pages17
JournalJournal of Immunology
Volume182
Issue number11
DOIs
Publication statusPublished - 1 Jun 2009
Externally publishedYes

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