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T-bet Knockout Prevents Helicobacter felis-Induced Gastric Cancer¹

Calin Stoicov^*, Xueli Fan^*, Jian Hua Liu^*, Glennice Bowen^*, Mark Whary, Evelyn Kurt-Jones^* and JeanMarie Houghton^2,,

^* Department of Medicine, University of Massachusetts Medical School, Worcester MA 01635; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139; and Department of Medicine, Division of Gastroenterology, and Department of Cancer Biology, University of Massachusetts Medical School, Worcester MA 01635

Helicobacter infection is the primary risk factor for gastric cancer, with the cytokine environment within the gastric mucosa the strongest predictor of disease risk. Elevated TNF-, IL-1β, and low IL-10 are associated with the highest risk. In this study, we used C57BL/6 mice to identify T-bet as a central regulator of the cytokine environment during Helicobacter felis infection. We infected male and female C57BL/6 and C57BL/6-T-bet knockout (KO) liter mates with H. felis and examined the bacterial colonization, immune response, and mucosal damage at varying time points. T-bet KO mice maintained infection for 15 mo at similar levels to wild-type mice. Infection and immune response did not differ between male and female mice. Despite sustained infection, T-bet KO mice respond with a blunted Th1 response associated with preservation of parietal and chief cells and protection from the development of gastric cancer. Unexpectedly, T-bet KO mice develop a gastric environment that would not be expected based on the phenotype of T-bet KO CD4 cells alone. T-bet KO mice respond to H. felis infection with a markedly blunted IL-1β and TNF- and elevated IL-10 levels. Activity of this one master regulator modulates the expression of the key gastric mucosal cytokines associated with gastric cancer and may be a target for therapy to restore immune balance clinically in patients at risk for gastric cancer.

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 work was supported by National Institutes of Health Grant RO1 CA113564 (to J.H.).

² Address correspondence and reprint requests to Dr. JeanMarie Houghton, Department of Medicine, University of Massachusetts Medical School, LRB 209, 364 Plantation Street, Worcester, MA 01635. E-mail address: jeanmarie.houghton{at}umassmed.edu

³ Abbreviations used in this paper: KO, knockout; WT, wild type.