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The CD4⁺ T Cell-Mediated IFN- Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk¹

Ayca Sayi^2,*, Esther Kohler^2,*, Iris Hitzler^2,*, Isabelle Arnold^*, Reto Schwendener^*, Hubert Rehrauer and Anne Müller^3,*

^* Institute of Molecular Cancer Research and Functional Genomics Center Zurich, University of Zurich, Zurich, Switzerland

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- 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-, 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- 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- in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was funded by grants from Schweizer Nationalfonds (3100A0-113452), the UBS Foundation (BA29 S8Q7-DZZ 969/A), and the Nils and Desiree Yde Stiftung to A.M. Additional funding was supplied by the University Research Priority Program in Systems Biology/Functional Genomics and the Institute of Molecular Cancer Research.

² A.S., E.K., and I.H. contributed equally to this work.

³ Address correspondence and reprint requests to Prof. Dr. Anne Müller, Institute of Molecular Cancer Research, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland. E-mail address: mueller{at}imcr.unizh.ch

⁴ Abbreviations used in this paper: PCNA, proliferating cell nuclear Ag; IP-10, IFN--inducible protein 10.

⁵ The online version of this article contains supplemental material.