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

dc.contributor.authorCarbo, Adriaen
dc.contributor.authorOlivares-Villagomez, Danyviden
dc.contributor.authorHontecillas, Raquelen
dc.contributor.authorBassaganya-Riera, Josepen
dc.contributor.authorChaturvedi, Rupeshen
dc.contributor.authorPiazuelo, M. Blancaen
dc.contributor.authorDelgado, Albertoen
dc.contributor.authorWashington, M. Kayen
dc.contributor.authorWilson, Keith T.en
dc.contributor.authorAlgood, Holly M. Scotten
dc.description.abstractThe 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-gamma) and IL-17 during chronic H. pylori infection. The model predicted activated expression of T-bet and ROR gamma t 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.en
dc.description.notesFlow cytometry experiments were performed in the VUMC Flow Cytometry Shared Resource. The VUMC Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (P30DK058404).; This work has been funded through Vanderbilt University Medical Center's Digestive Disease Research Center supported by National Institutes of Health grants P30DK058404 (Pilot projects awarded to H. M. S. A. and D.O.-V.), R01DK053620 (to K. T. W.), and K01AT007324 (to R. C.), NIAID contract no. HHSN272201000056C to J.B.-R., and funds from the Nutritional Immunology and Molecular Medicine Laboratory. This work has also been funded by a VA Career Development Award (to H. M. S. A.) and Merit Review grants IBX000915A (to H. M. S. A.) and 1I01BX001453 (to K. T. W.) from the Office of Medical Research, Department of Veterans Affairs.en
dc.description.sponsorshipVanderbilt Ingram Cancer Center [P30 CA68485]en
dc.description.sponsorshipVanderbilt Digestive Disease Research Center [P30DK058404]en
dc.description.sponsorshipVanderbilt University Medical Center's Digestive Disease Research Center - National Institutes of Health [P30DK058404, R01DK053620, K01AT007324]en
dc.description.sponsorshipNIAID [HHSN272201000056C]en
dc.description.sponsorshipNutritional Immunology and Molecular Medicine Laboratoryen
dc.description.sponsorshipVA Career Development Awarden
dc.description.sponsorshipOffice of Medical Research, Department of Veterans Affairs [IBX000915A, 1I01BX001453]en
dc.publisherAmerican Society for Microbiologyen
dc.rightsCreative Commons Attribution-NonCommercial-ShareAlike 3.0 Unporteden
dc.titleSystems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4(+) T Cell Responses during Chronic Helicobacter pylori Infectionen
dc.typeArticle - Refereeden


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