{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:34:28Z","timestamp":1792704868631,"version":"4.5.0"},"reference-count":52,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T00:00:00Z","timestamp":1405987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2014,8,29]],"date-time":"2014-08-29T00:00:00Z","timestamp":1409270400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2014,8,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The development of gastritis during\n                    <jats:named-content content-type=\"genus-species\">Helicobacter pylori<\/jats:named-content>\n                    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\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    infection, we combined mathematical modeling of CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell differentiation with\n                    <jats:italic>in vivo<\/jats:italic>\n                    mechanistic studies. We infected IL-21-deficient and wild-type mice with\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    strain SS1 and assessed colonization, gastric inflammation, cellular infiltration, and cytokine profiles. Chronically\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    -infected IL-21-deficient mice had higher\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    colonization, significantly less gastritis, and reduced expression of proinflammatory cytokines and chemokines compared to these parameters in infected wild-type littermates. These\n                    <jats:italic>in vivo<\/jats:italic>\n                    data were used to calibrate an\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    infection-dependent, CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell-specific computational model, which then described the mechanism by which IL-21 activates the production of interferon gamma (IFN-\u03b3) and IL-17 during chronic\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    infection. The model predicted activated expression of T-bet and ROR\u03b3t 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\n                    <jats:sup>+<\/jats:sup>\n                    splenocyte-specific\n                    <jats:italic>tbx21<\/jats:italic>\n                    and\n                    <jats:italic>rorc<\/jats:italic>\n                    expression, reduced phosphorylation of STAT1 and STAT3, and an increase in CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell-specific IL-10 expression in\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    -infected IL-21-deficient mice. Our results indicate that IL-21 regulates Th1 and Th17 effector responses during chronic\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    infection in a STAT1- and STAT3-dependent manner, therefore playing a major role controlling\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    infection and gastritis\n                    <jats:italic>.<\/jats:italic>\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    <jats:named-content content-type=\"genus-species\">Helicobacter pylori<\/jats:named-content>\n                    is the dominant member of the gastric microbiota in more than 50% of the world\u2019s population.\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    colonization has been implicated in gastritis and gastric cancer, as infection with\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    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\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    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\n                    <jats:named-content content-type=\"genus-species\">H. pylori<\/jats:named-content>\n                    as an alternative to aggressive antibiotics.\n                  <\/jats:p>","DOI":"10.1128\/mbio.01243-14","type":"journal-article","created":{"date-parts":[[2014,7,22]],"date-time":"2014-07-22T20:25:05Z","timestamp":1406060705000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":48,"title":["Systems Modeling of the Role of Interleukin-21 in the Maintenance of Effector CD4\n                    <sup>+<\/sup>\n                    T Cell Responses during Chronic Helicobacter pylori Infection"],"prefix":"10.1128","volume":"5","author":[{"given":"Adria","family":"Carbo","sequence":"first","affiliation":[{"name":"Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA"},{"name":"Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyvid","family":"Olivares-Villag\u00f3mez","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Hontecillas","sequence":"additional","affiliation":[{"name":"Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA"},{"name":"Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Bassaganya-Riera","sequence":"additional","affiliation":[{"name":"Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA"},{"name":"Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupesh","family":"Chaturvedi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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