The development of
gastritis during Helicobacter pylori
infection is dependent on an activated adaptive immune response orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to
gastritis and control of
infection are still under investigation. To investigate the role of
interleukin-21 (IL-21) in the gastric mucosa during H. pylori
infection, we combined mathematical modeling of CD4(+) T cell differentiation with in vivo mechanistic studies. We infected IL-21-deficient and wild-type mice with H. pylori strain SS1 and assessed colonization, gastric
inflammation, cellular infiltration, and
cytokine profiles. Chronically H. pylori-infected IL-21-deficient mice had higher H. pylori colonization, significantly less
gastritis, and reduced expression of proinflammatory
cytokines and
chemokines compared to these parameters in infected wild-type littermates. These in vivo data were used to calibrate an H. pylori
infection-dependent, CD4(+) T cell-specific computational model, which then described the mechanism by which
IL-21 activates the production of
interferon gamma (IFN-γ) and
IL-17 during chronic H. pylori
infection. The model predicted activated expression of T-bet and RORγt and the phosphorylation of STAT3 and STAT1 and suggested a potential role of
IL-21 in the modulation of
IL-10. Driven by our modeling-derived predictions, we found reduced levels of CD4(+) splenocyte-specific tbx21 and rorc expression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4(+) T cell-specific
IL-10 expression in H. pylori-infected IL-21-deficient mice. Our results indicate that
IL-21 regulates Th1 and Th17 effector responses during chronic H. pylori
infection in a STAT1- and STAT3-dependent manner, therefore playing a major role controlling H. pylori
infection and
gastritis. Importance: Helicobacter pylori is the dominant member of the gastric microbiota in more than 50% of the world's population. H. pylori colonization has been implicated in
gastritis and
gastric cancer, as
infection with H. pylori is the single most common risk factor for
gastric cancer. Current data suggest that, in addition to bacterial
virulence factors, the magnitude and types of immune responses influence the outcome of colonization and
chronic infection. This study uses a combined computational and experimental approach to investigate how
IL-21, a proinflammatory T cell-derived
cytokine, maintains the chronic proinflammatory T cell immune response driving chronic
gastritis during H. pylori
infection. This research will also provide insight into a myriad of other infectious and
immune disorders in which
IL-21 is increasingly recognized to play a central role. The use of IL-21-related
therapies may provide treatment options for individuals chronically colonized with H. pylori as an alternative to aggressive
antibiotics.