Helicobacter pylori Infection in a Pig Model Is Dominated by Th1 and Cytotoxic CD8⁺T Cell Responses

Abstract

Helicobacter pylori is the dominant member of the gastric microbiota and colonizes the stomach of more than 50% of the human population worldwide (1). H. pylori colonization usually does not cause illness, since 85% of infected people remain asymptomatic throughout life, but infection with strains bearing the cag (cytotoxin-associated gene) pathogenicity island can result in peptic ulcer disease, gastric lymphoma, and gastric adenocarcinoma, the second leading cause of cancer-related deaths, in 15% of infected individuals (2, 3). Conversely, there also is increasing evidence of H. pylori providing protection against esophageal and cardial pathologies (4-7), childhood asthma (8-10), childhood allergies (9, 11), and diabetes and obesity (12). This Gram-negative microaerophilic bacterium of the Epsilonproteobacteria has coevolved with humans for at least 50,000 years, indicating high adaptation capacity to the environmental niche of the human gastric mucosa and suggesting the ability to evade the immune system (13) through mechanisms that are incompletely understood. Infection with H. pylori in humans is associated mainly with a mucosal Th1 response, which is unsuccessful in clearing the bacteria from the stomach and can lead to more severe immunopathology (14). The pathogenicity of H. pylori is determined by various hostand pathogen-related factors, including the host's genetic background, age, and immune status and the bacterium's ability for antigenic variation, molecular mimicry, intracellular persistence, and expression of pathogenicity factors (15).Regulatory T (Treg) cells play a crucial role in H. pylori's ability to evade the immune system and persist in the gastric mucosa. Specifically, H. pylori can trigger a reprogramming of dendritic cells (DC) by downregulating major histocompatibility complex II (MHC-II) and inducing interleukin-10 (IL-10) and inhibiting IL-12 secretion, thereby inducing H. pylori-specific Treg cells (16)(17)(18). B cells also play a regulatory role by promoting IL-10 production in cocultured CD4 ϩ cells and subsequent conversion into a T T lymphocytes were found in the gastric epithelium and lamina propria (LP) of H. pylori-infected children with grade I to III gastritis (22, 23). Furthermore, the CD8 ϩ HLA-DR ϩ chronically activated memory T cell subset was expanded in peripheral blood of H. pylori-colonized children with duodenal ulcers (24), suggesting a role for CD8 ϩ T cells in H. pylori-mediated pathology. The majority of in vivo studies on the host responses to H. pylori are based on mouse models; however, in contrast to human

Novel insights on the role of CD8+ T cells and cytotoxic responses duringHelicobacter pyloriinfection

“…31 Comparable to immune responses observed in humans, our pig model also shows the infiltration of Foxp3+ T cells into the gastric mucosa. 30 Overall these findings corroborate that the pig model of H. pylori infection closely resembles human pathology. Thus, it has the potential to shed new light on host-H. pylori interactions and help developing novel treatment modalities.…”

“…These phenotypic changes correlated with upregulation of IFNγ, and markers of cytotoxic function like granzyme A, B, perforin, and CD16. 30 Similar to H. pylori-mediated chronic gastritis in humans, our pig model shows that bacteria persist in the pig stomach at the expense of lesion development. One of the main features observed in this novel H. pylori pig model was the development of numerous large tertiary structures consisting of lymphoid aggregates in the stomach mucosa.…”

“…One of the main features observed in this novel H. pylori pig model was the development of numerous large tertiary structures consisting of lymphoid aggregates in the stomach mucosa. 30 These changes were described in the stomachs of humans that were experimentally infected with H. pylori, and were still detectable, although of smaller size, after antibiotic therapy to eliminate the bacteria. 28 Moreover, a recent study describes the recruitment of DC-LAMP+ dendritic cells to gastric lymphoid follicles in stomach specimens obtained from H. pylori carriers.…”

Impact factors that modulate gastric cancer risk in Helicobacter pylori‐infected rodent models

“…Rodents and primates are the primary models used in H pylori ‐related studies. Helicobacter species can successfully colonize many animal species (eg, monkeys, pigs, cats, and dogs) . Primates have similar physiologies to that of humans; however, they are rarely used to construct H pylori ‐infected models due to their poor availability and high cost.…”

Systems-wide analyses of mucosal immune responses toHelicobacter pyloriat the interface between pathogenicity and symbiosis

“…99 We have recently demonstrated the expansion of circulating NK cells, CD8C T cells and concomitant increases in cytotoxic markers including CD16, granzyme B and perforin in a pig model of H. pylori infection. 100 Thus, a cytotoxic cell response might play a major role in H. pylorimediated pathology at least in part due to the cytokine response induced by the bacterium.…”