The role of Th cell subsets in the control of Helicobacter infections and in T cell-driven gastric immunopathology

Abstract

Chronic infection with the gastric bacterial pathogen Helicobacter pylori causes gastric adenocarcinoma in a particularly susceptible fraction of the infected population. The intestinal type of gastric cancer is preceded by a series of preneoplastic lesions that are of immunopathological origin, and that can be recapitulated by experimental infection of C57BL/6 mice with Helicobacter species. Several lines of evidence suggest that specific T cell subsets and/or their signature cytokines contribute to the control of Helicobacter infections on the one hand, and to the associated gastric preneoplastic pathology on the other. Here, we have used virulent H. pylori and H. felis isolates to infect mice that lack α/β T cells due to a targeted deletion of the T cell receptor β-chain, or are deficient for the unique p35 and p19 subunits of the Th1- and Th17-polarizing cytokines interleukin (IL)-12 and IL-23, respectively. We found that α/β T cells are absolutely required for Helicobacter control and for the induction of gastric preneoplastic pathology. In contrast, neither IL-12-dependent Th1 nor IL-23-dependent Th17 cells were essential for controlling the infection; IL-12p35-/- and IL-23p19-/- mice did not differ significantly from wild type animals with respect to Helicobacter colonization densities. Gastritis and gastric preneoplastic pathology developed to a similar extent in all three strains upon H. felis infection; in the H. pylori infection model, IL-23p19-/- mice exhibited significantly less gastritis and precancerous pathology. In summary, the results indicate that neither Th1 nor Th17 cells are by themselves essential for Helicobacter control; the associated gastric pathology is reduced only in the absence of Th17-polarizing IL-23, and only in the H. pylori, but not the H. felis infection model. The results thus suggest the involvement of other, as yet unknown T cell subsets in both processes.

Helicobacter heilmannii sensu lato: An overview of the infection in humans

“…The major exception is H. felis for which experimental models of infection have existed since the early 1990's, and for which different mice strains have been well-established as models of chronic gastritis [86] , gastric atrophy [87][88][89] , gastric MALT lymphoma [60] , and gastric carcinoma [90,91] . Infection with H. felis in these models are often also used to study the pathogenesis of infection and the host immune response to H. pylori [92][93][94][95] . [63,[96][97][98][99] .…”

Polymorphism in the Helicobacter pylori CagA and VacA toxins and disease

“…83 Not only can CagA induce cell scattering and elongation in a phosphorylation-dependent manner, CagA can also initiate this process in a phosphorylation independent the absence of the Th17 polarizing cytokine IL-23, IL-23p19 -/-mice exhibit significantly less gastritis and precancerous lesions, while IL-23 -/-H. pylori infected mice show decreased gastritis, decreases in the cytokines IL-17 and IFN-γ, and concomitant increases in bacterial burden. 58,59 IL-23 therefore appears to contribute to gastric pathology through activation of Th1/Th17 immune responses that control H. pylori infection by initiating inflammation and controlling the degree of gastritis. 58,59 The results from these animal experiments have also been extrapolated to human samples.…”

“…58,59 IL-23 therefore appears to contribute to gastric pathology through activation of Th1/Th17 immune responses that control H. pylori infection by initiating inflammation and controlling the degree of gastritis. 58,59 The results from these animal experiments have also been extrapolated to human samples. Analysis of patients with a past, but not current, H. pylori infection shows persistent H. pylori specific Th17 responses.…”

“…Indeed, the absence of lymphocytes results in resistance to gastritis. 53,58 To study the role of the Western EPIYA motif in CagA induced carcinogenesis, a second transgenic mouse model was also developed. 121 Expression of CagA containing the EPIYA-ABCCC motif in these animals that arises from these studies is that CagA is first phosphorylated by c-Src at the EPIYA-C or -D motif, followed by phosphorylation of the EPIYA-A or -B motif by c-Abl.…”

The synergy of Helicobacter pylori and lipid metabolic disorders in induction of Th17-related cytokines in human gastric cancer

“…[2,7,8] Considerable studies have demonstrated that a mixed response of Th1 and Th17 cells plays a critical role in H. pylori-induced inflammatory gastric diseases and cancer. [9,10] The phenotypes of T helper subsets are determined by the local cytokine milieu and their lineage-specific transcription factors. [11][12][13] H. pylori elicits Th1 response to produce interferon-γ and tumor necrosis factor-α causing chronic gastritis and ulcers.…”