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.
Highlights
Persistent colonization of the human gastric mucosa with the Gram-negative bacterial pathogen Helicobacter pylori causes gastritis (Marshall and Warren, 1984) and predisposes carriers to a high risk of developing gastric and duodenal ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma (Parsonnet et al, 1991, 1994; Parsonnet and Isaacson, 2004; Pritchard and Crabtree, 2006)
(1) Mice lacking a B and/or T lymphocyte compartment (Rag-1−/−, TCR-β−/−) are resistant to gastritis induced by Helicobacter infection, and the adoptive transfer of CD4+ effector T cells from infected wild type (WT) donors to infected TCR-β−/− recipients is in itself sufficient to restore the full range of preneoplastic pathology (Roth et al, 1999; Smythies et al, 2000; Sayi et al, 2009, 2011; Arnold et al, 2011)
To assess whether the relative resistance to the earliest detectable histopathological symptoms of Helicobacter infection translates into long-term protection from disease, we infected WT C57BL/6 and TCR-β−/− mice with H. felis for 3 months; we chose H. felis due to its documented virulence in mice (Fox et al, 2002, 2003; Sayi et al, 2009)
Summary
Persistent colonization of the human gastric mucosa with the Gram-negative bacterial pathogen Helicobacter pylori causes gastritis (Marshall and Warren, 1984) and predisposes carriers to a high risk of developing gastric and duodenal ulcers, gastric mucosa-associated lymphoid tissue lymphoma, and gastric adenocarcinoma (Parsonnet et al, 1991, 1994; Parsonnet and Isaacson, 2004; Pritchard and Crabtree, 2006). H. pylori infection-associated gastric cancer develops via a sequence of histologically defined preneoplastic lesions, all of which have been linked independently to gastric cancer risk (Correa, 1995; Fox and Wang, 2007). Experimental infection of Mongolian gerbils (Rieder et al, 2005; Wiedemann et al, 2009) or C57BL/6 mice (Fox et al, 2002, 2003) with Helicobacter species recapitulates the sequential development of chronic gastritis, atrophic gastritis, epithelial hyperplasia, and intestinal metaplasia, all of which are hallmark lesions in a subset of susceptible human H. pylori carriers (Correa, 1995; Fox and Wang, 2007). Observational studies in human carriers support the view that pathogenic T cells are instrumental in inducing H. pyloriassociated lesions: Robinson et al (2008) showed for instance that patients with peptic ulcer disease exhibited stronger Th1 and Th2 www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
