The C-Terminally Encoded, MHC Class II-Restricted T Cell Antigenicity of the Helicobacter pylori Virulence Factor CagA Promotes Gastric Preneoplasia

Abstract

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.

Interferon-γ promotes gastric lymphoid follicle formation but not gastritis in Helicobacter-infected BALB/c mice

“…There is clear evidence that the default T helper cell responses of mouse strains contribute to inflammation severity [13, 21, 26, 36, 40, 41]. However, other immunological characteristics intrinsic to specific mouse strains, such as their major histocompatibility complex haplotype, are also likely to be important [3, 20, 21, 23, 30, 35, 42, 43]. …”

Helicobacter Pylori Utilizes DNA Shuffling to Modulate the Gastric Inflammatory Response

“…There is now substantial evidence that the Cag system provides a selective advantage for an infecting population; for example, by recruiting iron through inducing CagA-dependent epithelial polarity defects and thus facilitating apical surface colonization [18]. On the other hand, the same system induces immune responses that restrict colonization by T4SS-producing cells, for instance via CagA-specific T cells [19]. Taken together, it is possible that the colonizing population becomes unstable either by too many T4SS producers or by too many T4SS-negative mutants utilizing the growth-promoting effects of T4SS producers without supporting them.…”

CD4+ T-cell epitope prediction using antigen processing constraints

“…However, immunization with CD4+ epitope peptides has also been shown to cause immunopathology and death [6, 7]. These studies emphasize the critical need for further analysis of CD4+ T-cell responses, which would be greatly facilitated by accurate epitope prediction.…”