Tolerance Rather Than Immunity Protects From Helicobacter pylori–Induced Gastric Preneoplasia

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 140; no. 1; pp. 199 - 209.e8
• Main Authors: Arnold, Isabelle C., Lee, Josephine Y., Amieva, Manuel R., Roers, Axel, Flavell, Richard A., Sparwasser, Tim, Müller, Anne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2011
• Subjects: Animals; Bacterial Secretion Systems - immunology; Female; Gastric Cancer; Gastric Mucosa - microbiology; Gastric Mucosa - pathology; Gastritis, Atrophic - microbiology; Gastritis, Atrophic - pathology; Gastroenterology and Hepatology; Genomic Islands - immunology; Helicobacter Infections - immunology; Helicobacter Infections - microbiology; Helicobacter Infections - pathology; Helicobacter pylori; Helicobacter pylori - immunology; Hyperplasia - immunology; Hyperplasia - microbiology; Immune Tolerance; Male; Metaplasia - immunology; Metaplasia - microbiology; Mice; Mice, Inbred C57BL; Neonatal Tolerance; Precancerous Conditions - immunology; Precancerous Conditions - microbiology; Regulatory T Cells; Stomach Diseases - immunology; Stomach Diseases - microbiology; Stomach Diseases - pathology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - microbiology; Neonatal Tolerance; CagA; Treg; TCRβ; IL-10; DT; SS1; IFN-γ; Regulatory T Cells; Helicobacter pylori; Gastric Cancer; dnTβRII; PAI; TGF-β; ELISA; PMSS1; dominant-negative form of the TGF-β receptor II; transforming growth factor β; interleukin-10; pathogenicity island; pre-mouse Sydney strain 1; interferon gamma; Sydney strain 1; cytotoxin-associated gene A; regulatory T cell; enzyme-linked immunosorbent assay; diphtheria toxin; T-cell receptor-β
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2010.06.047

Chronic infection with the bacterial pathogen Helicobacter pylori causes gastric disorders, ranging from chronic gastritis to gastric adenocarcinoma. Only a subset of infected persons will develop overt disease; most remains asymptomatic despite lifelong colonization. This study aims to elucidate the differential susceptibility to H pylori that is found both across and within populations. We have established a C57BL/6 mouse model of H pylori infection with a strain that is capable of delivering the virulence factor cytotoxin-associated gene A (CagA) into host cells through the activity of a Cag-pathogenicity island–encoded type IV secretion system. Mice infected at 5–6 weeks of age with CagA + H pylori rapidly develop gastritis, gastric atrophy, epithelial hyperplasia, and metaplasia in a type IV secretion system–dependent manner. In contrast, mice infected during the neonatal period with the same strain are protected from preneoplastic lesions. Their protection results from the development of H pylori–specific peripheral immunologic tolerance, which requires transforming growth factor-β signaling and is mediated by long-lived, inducible regulatory T cells, and which controls the local CD4 + T-cell responses that trigger premalignant transformation. Tolerance to H pylori develops in the neonatal period because of a biased ratio of T-regulatory to T-effector cells and is favored by prolonged low-dose exposure to antigen. Using a novel CagA + H pylori infection model, we report here that the development of tolerance to H pylori protects from gastric cancer precursor lesions. The age at initial infection may thus account for the differential susceptibility of infected persons to H pylori–associated disease manifestations.