Abstract
Dendritic cells (DCs) play a major role in the innate immune response since they recognize a broad repertoire of PAMPs mainly via Toll-like receptors (TLRs). During Helicobacter pylori (H. pylori) infection, TLRs have been shown to be important to control cytokine response particularly in murine DCs. In the present study we analyzed the effect of blocking TLRs on human DCs. Co-incubation of human DCs with H. pylori resulted in the release of the pro-inflammatory cytokines IL-12p70, IL-6 and IL-10. Release of IL-12p70 and IL-10 was predominantly influenced when TLR4 signaling was blocked by adding specific antibodies, suggesting a strong influence on subsequent T cell responses through TLR4 activation on DCs. Co-incubation of H. pylori-primed DC with allogeneic CD4+ T cells resulted in the production of IFN-γ and IL-17A as well as the expression of Foxp3, validating a mixed Th1/Th17 and Treg response in vitro. Neutralization of TLR4 during H. pylori infection resulted in significantly decreased amounts of IL-17A and IFN-γ and reduced levels of Foxp3-expressing and IL-10-secreting T cells. Our findings suggest that DC cytokine secretion induced upon TLR4-mediated recognition of H. pylori influences inflammatory and regulatory T cell responses, which might facilitate the chronic bacterial persistence.
Highlights
Helicobacter pylori (H. pylori) is a gram-negative bacillus that selectively colonizes the human gastric mucosa
Blocking of Toll-like receptors (TLRs) signaling during H. pylori infection by using neutralizing antibodies affected the maturation status of Dendritic cells (DCs): the expression of CD86 and CD83 was significantly increased when TLR2 and TLR4 were blocked, whereas no effect was detected after inhibition of TLR5 (Figure 1)
Especially during H. pylori infection, DCs seem to play a special role in the initiation of adaptive immune responses, since increased numbers of activated DCs have been detected in the lamina propria of H. pylori-infected individuals [21], while in murine models DCs have been shown to induce H. pylori–specific adaptive immune responses [22]
Summary
Helicobacter pylori (H. pylori) is a gram-negative bacillus that selectively colonizes the human gastric mucosa. Despite the development of an acquired immune response, H. pylori can persistently colonize the stomach for decades. In the later course of the infection increased amounts of CD4+/CD25+ regulatory T cells (Tregs) expressing Foxp are observed [3]. This cell type is known to further suppress effector T cell responses, thereby enabling H. pylori persistence and pathology. The pathogenic persistence is presumably facilitated through the induction of tolerance. In this context, DCs have been show to play a crucial role. Beside their ability to enter the gastric epithelium in order to take up bacteria, DCs play an exceptional role in the regulation of T cell-mediated immune responses which are influenced by the strength of antigen presentation, intensity of costimulation [4] and by the milieu of secreted cytokines [5]
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