Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4 T Cell Responses during Chronic Helicobacter pylori Infection

ABSTRACT The development of gastritis duringHelicobacter pylori infection is dependent on an activated adaptive immune re-sponse orchestrated by T helper (Th) cells. However, the relative contributions of the Th1 and Th17 subsets to gastritis and con-trol of infection are still under investigation. To investigate the role of interleukin-21 (IL-21) in the gastric mucosa duringH. py-lori infection, we combined mathematical modeling of CD4 T cell differentiation with in vivomechanistic studies. We infected IL-21-deficient and wild-type mice withH. pylori strain SS1 and assessed colonization, gastric inflammation, cellular infiltra-tion, and cytokine profiles. ChronicallyH. pylori-infected IL-21-deficient mice had higherH. 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 anH. pylori infection-dependent, CD4 T cell-specific computa-tional model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-) and IL-17 during chronicH. pylori infection. The model predicted activated expression of T-bet and RORt 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 predic-tions, 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 inH. pylori-infected IL-21-deficient mice. Our results indicat