Helicobacter pylori Cholesteryl α-Glucosides Contribute to Its Pathogenicity and Immune Response by Natural Killer T Cells

Approximately 10-15% of individuals infected with Helicobacter pylori will develop ulcer disease (gastric or duodenal ulcer), while most people infected with H. pylori will be asymptomatic. The majority of infected individuals remain asymptomatic partly due to the inhibition of synthesis of cholesteryl alpha-glucosides in H. pylori cell wall by alpha 1,4-GlcNAc-capped mucin O-glycans, which are expressed in the deeper portion of gastric mucosa. However, it has not been determined how cholesteryl alpha-glucosyltransferase (alpha CgT), which forms cholesteryl alpha-glucosides, functions in the pathogenesis of H. pylori infection. Here, we show that the activity of alpha CgT from H. pylori clinical isolates is highly correlated with the degree of gastric atrophy. We investigated the role of cholesteryl alpha-glucosides in various aspects of the immune response. Phagocytosis and activation of dendritic cells were observed at similar degrees in the presence of wild-type H. pylori or variants harboring mutant forms of alpha CgT showing a range of enzymatic activity. However, cholesteryl alpha-glucosides were recognized by invariant natural killer T (iNKT) cells, eliciting an immune response in vitro and in vivo. Following inoculation of H. pylori harboring highly active alpha CgT into iNKT cell-deficient (J alpha 18(-/-)) or wild-type mice, bacterial recovery significantly increased in J alpha 18(-/-) compared to wildtype mice. Moreover, cytokine production characteristic of Th1 and Th2 cells dramatically decreased in J alpha 18(-/-) compared to wild-type mice. These findings demonstrate that cholesteryl alpha-glucosides play critical roles in H. pylori-mediated gastric inflammation and precancerous atrophic gastritis.