Helicobacter pylori directs tolerogenic programming of dendritic cells.

Our laboratory has shown that Helicobacter pylori infection in mice triggers an increase in the number of subepithelial lamina propria CD11c(+) dendritic cells with luminal projections. The physical characteristic of these cells is consistent with their ability to traverse epithelial tight junctions as reported by Maria Recigno.3 Gastric CD103(+) dendritic cells, which are known to induce mucosal regulatory T cells, were also increased in number, raising the question whether H. pylori infection induces a regulatory T cell-skewed response by way of a bacteria-dendritic cell interaction. In fact, bone marrow-derived dendritic cells underwent tolerogenic programming, skewing the balance between effector and regulatory T cell responses towards regulatory T cell differentiation in a transforming growth factor-β- and interleukin-10-dependent manner. Depletion of regulatory T cell numbers augmented H. pylori-specific effector helper T cell responses, which correlated with a lower degree of H. pylori colonization. These results suggest H. pylori is capable of inducing a regulatory T cell-skewed response that limits the host's ability to eradicate the bacteria, allowing the H. pylori infection to persist. To better understand the mechanism of H. pylori tolerogenic programming we compared the differential expressions of 34 genes critical for dendritic cell function in bone marrow-derived dendritic cells pulsed with live H. pylori or other Gram-negative bacteria (e.g., Escherichia coli, Acinetobacter lwoffii). Our data imply that H. pylori targets the Toll-like receptor 2 pathway to induce a regulatory T cell-skewed response. In addition, we show that H. pylori-pulsed dendritic cells are capable of inducing the conversion of naïve T cells to regulatory T cells. These observations are evidence of a unique tolerogenic program in dendritic cells that involves active editing of the immune response by H. pylori, favoring its persistence in the gastric mucosa.