The C-terminally encoded, MHC class II-restricted T cell antigenicity of the helicobacter pylori virulence factor CagA promotes gastric preneoplasia
| Autor: | Anne Müller, Else Marie Agger, Iris Hitzler, Daniela B. Engler, Mathias Oertli, Isabelle C. Arnold |
|---|---|
| Přispěvatelé: | University of Zurich, Müller, Anne |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Adoptive cell transfer
Receptors Antigen T-Cell alpha-beta T-Lymphocytes Epitopes T-Lymphocyte Epitope Mice 0302 clinical medicine Immunology and Allergy Mice Knockout 0303 health sciences biology Virulence 10061 Institute of Molecular Cancer Research Adoptive Transfer 3. Good health medicine.anatomical_structure Bacterial Vaccines Host-Pathogen Interactions 2723 Immunology and Allergy T cell Immunology Helicobacter Infections 03 medical and health sciences Antigen Bacterial Proteins Stomach Neoplasms MHC class I medicine CagA Animals Humans Secretion 030304 developmental biology Antigens Bacterial 2403 Immunology Helicobacter pylori Histocompatibility Antigens Class II Th1 Cells biology.organism_classification bacterial infections and mycoses Virology digestive system diseases Mice Inbred C57BL Animals Newborn Gastric Mucosa biology.protein 570 Life sciences Immunization 030215 immunology |
| Zdroj: | Journal of immunology (Baltimore Md. : 1950) |
| Popis: | 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+ H. pylori infection that the only known protein substrate of the Cag-PAI–encoded 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’s 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. |
| Databáze: | OpenAIRE |
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