T-bet Knockout Prevents Helicobacter felis-Induced Gastric Cancer

• Published in: The Journal of immunology (1950) Vol. 183; no. 1; pp. 642 - 649
• Main Authors: Stoicov, Calin, Fan, Xueli, Liu, Jian Hua, Bowen, Glennice, Whary, Mark, Kurt-Jones, Evelyn, Houghton, JeanMarie
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.07.2009
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - microbiology; Adenocarcinoma - prevention & control; Animals; Female; Gastric Mucosa - immunology; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Genetic Predisposition to Disease; Helicobacter felis - immunology; Helicobacter Infections - immunology; Helicobacter Infections - pathology; Helicobacter Infections - prevention & control; Interleukin-1beta - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Stomach Neoplasms - immunology; Stomach Neoplasms - microbiology; Stomach Neoplasms - prevention & control; T-Box Domain Proteins - deficiency; T-Box Domain Proteins - genetics; T-Box Domain Proteins - physiology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900511

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-alpha, IL-1beta, 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) litter 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-1beta and TNF-alpha 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.