Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4
+
T Cell Responses during Chronic Helicobacter pylori Infection
Authors: Carbo Adria , Olivares-Villagómez Danyvid , Hontecillas Raquel , Bassaganya-Riera Josep , Chaturvedi Rupesh , Piazuelo M. Blanca , Delgado Alberto , Washington M. Kay , Wilson Keith T. , Algood Holly M. Scott 
Published: July 2014

ABSTRACT

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.