Chronic Exposure to<i>Helicobacter pylori</i>Impairs Dendritic Cell Function and Inhibits Th1 Development

<jats:title>ABSTRACT</jats:title><jats:p><jats:italic>Helicobacter pylori</jats:italic>causes chronic gastric infection that affects the majority of the world's population. Despite generating an inflammatory response, the immune system usually fails to clear the infection. Since dendritic cells (DCs) play a pivotal role in shaping the immune response, we investigated the effects of<jats:italic>H. pylori</jats:italic>on DC function. We have demonstrated that<jats:italic>H. pylori</jats:italic>increased the expression of activation markers on DCs while upregulating the inhibitory B7 family molecule, PD-L1. Functionally,<jats:italic>H. pylori</jats:italic>-treated DCs resulted in the production of interleukin-10 (IL-10) and IL-23 but not of alpha interferon (IFN-α). While very little or no IL-12 was produced to<jats:italic>H. pylori</jats:italic>alone, simultaneous ligation of CD40 on DCs induced IL-12 release. We also demonstrated that DCs treated with<jats:italic>H. pylori</jats:italic>-induced IFN-γ production by allogeneic naive T cells. However, stimulation of DCs with<jats:italic>H. pylori</jats:italic>for an extended period of time impaired their ability to produce cytokines after CD40 ligation and limited their ability to promote IFN-γ release, suggesting that the DCs had become exhausted by the prolonged stimulation. The effect of chronic infection with<jats:italic>H. pylori</jats:italic>on DC function was further investigated by focusing on DC development. Demonstrating that monocytes differentiated into DCs in the presence of<jats:italic>H. pylori</jats:italic>exhibited an exhausted phenotype with an impaired ability to produce IL-12 and a downregulation of CD1a. Our results raise the possibility that in chronic<jats:italic>H. pylori</jats:italic>infection DCs become exhausted after prolonged antigen exposure leading to suboptimal Th1 development. This effect may contribute to persistence of<jats:italic>H. pylori</jats:italic>infection.</jats:p>