{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T14:02:16Z","timestamp":1774792936578,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2011,6,1]],"date-time":"2011-06-01T00:00:00Z","timestamp":1306886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Chronic infection with the human bacterial pathogen Helicobacter pylori causes gastritis and predisposes carriers to an increased gastric cancer risk. Consequently, H. pylori-specific vaccination is widely viewed as a promising strategy of gastric cancer prevention. H. pylori strains harboring the Cag pathogenicity island (PAI) are associated with particularly unfavorable disease outcomes in humans and experimental rodent models. We show in this study using a C57BL\/6 mouse model of Cag-PAI+ \u00a0H. pylori infection that the only known protein substrate of the Cag-PAI\u2013encoded type IV secretion system, the cytotoxin-associated gene A (CagA) protein, harbors MHC class II-restricted T cell epitopes. Several distinct nonoverlapping epitopes in CagA\u2019s central and C-terminal regions were predicted in silico and could be confirmed experimentally. CagA+ infection elicits CD4+ T cell responses in mice, which are strongly enhanced by prior mucosal or parenteral vaccination with recombinant CagA. The adoptive transfer of CagA-specific T cells to T cell-deficient, H. pylori-infected recipients is sufficient to induce the full range of preneoplastic immunopathology. Similarly, immunization with a cholera toxin-adjuvanted, CagA+ whole-cell sonicate vaccine sensitizes mice to, rather than protects them from, H. pylori-associated gastric cancer precursor lesions. In contrast, H. pylori-specific tolerization by neonatal administration of H. pylori sonicate in conjunction with a CD40L-neutralizing Ab prevents H. pylori-specific, pathogenic T cell responses and gastric immunopathology. We conclude that active tolerization may be superior to vaccination strategies in gastric cancer prevention.<\/jats:p>","DOI":"10.4049\/jimmunol.1003472","type":"journal-article","created":{"date-parts":[[2011,4,26]],"date-time":"2011-04-26T03:29:30Z","timestamp":1303788570000},"page":"6165-6172","source":"Crossref","is-referenced-by-count":19,"title":["The C-Terminally Encoded, MHC Class II-Restricted T Cell Antigenicity of the <i>Helicobacter pylori<\/i> Virulence Factor CagA Promotes Gastric Preneoplasia"],"prefix":"10.1093","volume":"186","author":[{"given":"Isabelle C","family":"Arnold","sequence":"first","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Hitzler","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Engler","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathias","family":"Oertli","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Else Marie","family":"Agger","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Immunology, Statens Serum Institute , 2300 Copenhagen ,","place":["Denmark"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Zurich , 8057 Zurich ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2011,6,1]]},"reference":[{"key":"2025032411280287400_r1","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/S0140-6736(84)91816-6","article-title":"Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration","volume":"323","author":"Marshall","year":"1984","journal-title":"Lancet"},{"key":"2025032411280287400_r2","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1056\/NEJM199110173251603","article-title":"Helicobacter pylori infection and the risk of gastric carcinoma","volume":"325","author":"Parsonnet","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"2025032411280287400_r3","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1056\/NEJM199405053301803","article-title":"Helicobacter pylori infection and gastric lymphoma","volume":"330","author":"Parsonnet","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"2025032411280287400_r4","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1097\/01.mog.0000245539.50765.f6","article-title":"Helicobacter pylori and gastric cancer","volume":"22","author":"Pritchard","year":"2006","journal-title":"Curr. Opin. Gastroenterol."},{"key":"2025032411280287400_r5","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S1286-4579(03)00112-6","article-title":"Helicobacter in the developing world","volume":"5","author":"Frenck","year":"2003","journal-title":"Microbes Infect."},{"key":"2025032411280287400_r6","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S1473-3099(06)70627-2","article-title":"Helicobacter pylori and antimicrobial resistance: molecular mechanisms and clinical implications","volume":"6","author":"Gerrits","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"2025032411280287400_r7","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/S0264-410X(01)00401-7","article-title":"Quantifying the population impact of a prophylactic Helicobacter pylori vaccine","volume":"20","author":"Rupnow","year":"2001","journal-title":"Vaccine"},{"key":"2025032411280287400_r8","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1084\/jem.188.12.2277","article-title":"Immunization of mice with urease vaccine affords protection against Helicobacter pylori infection in the absence of antibodies and is mediated by MHC class II-restricted responses","volume":"188","author":"Ermak","year":"1998","journal-title":"J. Exp. Med."},{"key":"2025032411280287400_r9","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1084\/jem.191.9.1467","article-title":"The neutrophil-activating protein (HP-NAP) of Helicobacter pylori is a protective antigen and a major virulence factor","volume":"191","author":"Satin","year":"2000","journal-title":"J. Exp. Med."},{"key":"2025032411280287400_r10","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1016\/j.vaccine.2006.12.026","article-title":"Oral immunization with HpaA affords therapeutic protective immunity against H. pylori that is reflected by specific mucosal immune responses","volume":"25","author":"Nystr\u00f6m","year":"2007","journal-title":"Vaccine"},{"key":"2025032411280287400_r11","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/S0264-410X(97)00247-8","article-title":"Protection of mice against gastric colonization by Helicobacter pylori by single oral dose immunization with attenuated Salmonella typhimurium producing urease subunits A and B","volume":"16","author":"G\u00f3mez-Duarte","year":"1998","journal-title":"Vaccine"},{"key":"2025032411280287400_r12","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1136\/gut.2007.145839","article-title":"Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines","volume":"57","author":"Aebischer","year":"2008","journal-title":"Gut"},{"key":"2025032411280287400_r13","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/S0264-410X(01)00391-7","article-title":"Safety and immunogenicity of live recombinant Salmonella enterica serovar Typhi Ty21a expressing urease A and B from Helicobacter pylori in human volunteers","volume":"20","author":"Bumann","year":"2001","journal-title":"Vaccine"},{"key":"2025032411280287400_r14","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1053\/j.gastro.2008.05.054","article-title":"Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: a phase I study","volume":"135","author":"Malfertheiner","year":"2008","journal-title":"Gastroenterology"},{"key":"2025032411280287400_r15","first-page":"760","article-title":"Heightened inflammatory response and cytokine expression in vivo to cagA+ Helicobacter pylori strains","volume":"73","author":"Peek","year":"1995","journal-title":"Lab. Invest."},{"key":"2025032411280287400_r16","first-page":"2111","article-title":"Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach","volume":"55","author":"Blaser","year":"1995","journal-title":"Cancer Res."},{"key":"2025032411280287400_r17","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1053\/j.gastro.2003.08.033","article-title":"Meta-analysis of the relationship between cagA seropositivity and gastric cancer","volume":"125","author":"Huang","year":"2003","journal-title":"Gastroenterology"},{"key":"2025032411280287400_r18","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1126\/science.287.5457.1497","article-title":"Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion","volume":"287","author":"Odenbreit","year":"2000","journal-title":"Science"},{"key":"2025032411280287400_r19","doi-asserted-by":"crossref","first-page":"14559","DOI":"10.1073\/pnas.96.25.14559","article-title":"Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori","volume":"96","author":"Segal","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411280287400_r20","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1126\/science.1081919","article-title":"Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA","volume":"300","author":"Amieva","year":"2003","journal-title":"Science"},{"key":"2025032411280287400_r21","doi-asserted-by":"crossref","first-page":"e1000407","DOI":"10.1371\/journal.ppat.1000407","article-title":"Helicobacter pylori usurps cell polarity to turn the cell surface into a replicative niche","volume":"5","author":"Tan","year":"2009","journal-title":"PLoS Pathog."},{"key":"2025032411280287400_r22","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1073\/pnas.0711183105","article-title":"Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse","volume":"105","author":"Ohnishi","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032411280287400_r23","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1053\/j.gastro.2005.02.064","article-title":"Helicobacter pylori cag-type IV secretion system facilitates corpus colonization to induce precancerous conditions in Mongolian gerbils","volume":"128","author":"Rieder","year":"2005","journal-title":"Gastroenterology"},{"key":"2025032411280287400_r24","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1053\/j.gastro.2010.06.047","article-title":"Tolerance rather than immunity protects from Helicobacter pylori-induced gastric preneoplasia","volume":"140","author":"Arnold","year":"2011","journal-title":"Gastroenterology"},{"key":"2025032411280287400_r25","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.bbamem.2005.10.011","article-title":"Characterization of cationic liposomes based on dimethyldioctadecylammonium and synthetic cord factor from M. tuberculosis (trehalose 6,6\u2032-dibehenate)\u2014A novel adjuvant inducing both strong CMI and antibody responses","volume":"1718","author":"Davidsen","year":"2005","journal-title":"Biochim. Biophys. Acta."},{"key":"2025032411280287400_r26","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1365-2567.2007.02751.x","article-title":"Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection","volume":"124","author":"Agger","year":"2008","journal-title":"Immunology"},{"key":"2025032411280287400_r27","doi-asserted-by":"crossref","first-page":"7085","DOI":"10.4049\/jimmunol.0803293","article-title":"The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk","volume":"182","author":"Sayi","year":"2009","journal-title":"J. Immunol."},{"key":"2025032411280287400_r28","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.it.2005.06.002","article-title":"Control of peripheral T-lymphocyte tolerance in neonates and adults","volume":"26","author":"Arnold","year":"2005","journal-title":"Trends Immunol."},{"key":"2025032411280287400_r29","doi-asserted-by":"crossref","first-page":"771","DOI":"10.4049\/jimmunol.175.2.771","article-title":"Analysis of the underlying cellular mechanisms of anti-CD154-induced graft tolerance: the interplay of clonal anergy and immune regulation","volume":"175","author":"Quezada","year":"2005","journal-title":"J. Immunol."},{"key":"2025032411280287400_r30","doi-asserted-by":"crossref","first-page":"878","DOI":"10.4049\/jimmunol.1002269","article-title":"TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells","volume":"186","author":"Sayi","year":"2011","journal-title":"J. Immunol."},{"key":"2025032411280287400_r31","doi-asserted-by":"crossref","first-page":"5912","DOI":"10.1158\/0008-5472.CAN-10-0528","article-title":"Inhibition of ADP ribosylation prevents and cures helicobacter-induced gastric preneoplasia","volume":"70","author":"Toller","year":"2010","journal-title":"Cancer Res."},{"key":"2025032411280287400_r32","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1053\/j.gastro.2009.12.006","article-title":"Prostaglandin E2 prevents Helicobacter-induced gastric preneoplasia and facilitates persistent infection in a mouse model","volume":"138","author":"Toller","year":"2010","journal-title":"Gastroenterology"},{"key":"2025032411280287400_r33","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1586\/egh.10.6","article-title":"Advances in vaccination against Helicobacter pylori","volume":"4","author":"Velin","year":"2010","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"2025032411280287400_r34","first-page":"68","article-title":"Protective and pathogenic functions of T-cells are inseparable during the Helicobacter-host interaction","volume":"8","author":"Mueller","year":"2009","journal-title":"Discov. Med."},{"key":"2025032411280287400_r35","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1136\/gut.49.4.467","article-title":"Post-immunisation gastritis and Helicobacter infection in the mouse: a long term study","volume":"49","author":"Sutton","year":"2001","journal-title":"Gut"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/11\/6165\/61732484\/1003472.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/186\/11\/6165\/61732484\/1003472.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T18:04:47Z","timestamp":1743185087000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/186\/11\/6165\/7996553"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,6,1]]},"references-count":35,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2011,6,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1003472","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2011,6]]},"published":{"date-parts":[[2011,6,1]]}}}