The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells

Abstract

VacA is a pore-forming toxin that has long been known to induce vacuolization in gastric epithelial cells and to be linked to gastric disorders caused by H. pylori infection. Its role as a major colonization and persistence determinant of H. pylori is less well-understood. The purpose of this review is to discuss the various target cell types of VacA and its mechanism of action; specifically, we focus on the evidence showing that VacA targets myeloid cells and T-cells to directly and indirectly prevent H. pylori-specific T-cell responses and immune control of the infection. In particular, the ability of VacA-proficient H. pylori to skew T-cell responses towards regulatory T-cells and the effects of Tregs on H. pylori chronicity are highlighted. The by-stander effects of VacA-driven immunomodulation on extragastric diseases are discussed as well.

Keywords: T-cell priming; effector T-cells; immune tolerance; myeloid cells; persistent infection; professional antigen-presenting cells; regulatory T-cells.

Figure 1

VacA prevents phagosome maturation in professional antigen-presenting cells. Most strains of H. pylori express the secreted virulence factors VacA to affect phagosome maturation and lysosome fusion. The receptor for VacA on myeloid cells is not known. It has been proposed that H. pylori-containing phagosomes fail to mature and instead resemble early endosomes that have resisted lysosome fusion; this process appears to be specific to type I strains and is dependent on VacA expression [12]. Treatment with recombinant IFN-γ allows phagocytes to overcome their block in phagosome maturation and to kill intracellular type I strains of H. pylori.

Figure 2

H. pylori exerts immunomodulatory effects at extragastric sites. H. pylori exclusively inhabits the gastric mucosa but has systemic immunomodulatory effects that manifest in the airways, lower gastrointestinal tract, and possibly the skin. Gastric tissue-resident DCs presumably sample H. pylori antigens locally at the site of infection and subsequently migrate to the stomach-draining and mesenteric lymph nodes (MLNs), where they prime T-effector and regulatory T-cell responses. VacA is believed to skew this process towards Treg differentiation [2]. MLN-derived, H. pylori-induced Tregs enter the circulation and, due to cross-talk between the GI tract and lung immune systems, may accumulate in both the gastric mucosa and the lung. According to current models, allergen-specific Th2 cells in the lung are suppressed by H. pylori-induced Tregs via soluble mediators (such as IL-10) and contact-dependent mechanisms (reviewed in [43]). Tregs further suppress Th1 and Th17 responses directed against H. pylori in the gastric mucosa [30,44]. DC: dendritic cell; Th1/2/17: T-helper cell subsets; Treg: regulatory T-cell. Please note that, due to space restrictions, the MLN shown here is not in its correct anatomical location, which would be in the mesentery, linking the intestines to the abdominal wall.