Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity

dc.contributor.authorCarbo, Adriaen
dc.contributor.authorHontecillas, Raquelen
dc.contributor.authorKronsteiner, Barbaraen
dc.contributor.authorViladomiu, Monicaen
dc.contributor.authorPedragosa, Mireiaen
dc.contributor.authorLu, Pinylen
dc.contributor.authorPhilipson, Casandra W.en
dc.contributor.authorHoops, Stefanen
dc.contributor.authorMarathe, Madhaven
dc.contributor.authorEubank, Stephenen
dc.contributor.authorBisset, Keith R.en
dc.contributor.authorWendelsdorf, Katherineen
dc.contributor.authorJarrah, Abdul Salamen
dc.contributor.authorMei, Yongguoen
dc.contributor.authorBassaganya-Riera, Josepen
dc.description.abstractDifferentiation of CD4+ T cells into effector or regulatory phenotypes is tightly controlled by the cytokine milieu, complex intracellular signaling networks and numerous transcriptional regulators. We combined experimental approaches and computational modeling to investigate the mechanisms controlling differentiation and plasticity of CD4+ T cells in the gut of mice. Our computational model encompasses the major intracellular pathways involved in CD4+ T cell differentiation into T helper 1 (Th1), Th2, Th17 and induced regulatory T cells (iTreg). Our modeling efforts predicted a critical role for peroxisome proliferator-activated receptor gamma (PPARc) in modulating plasticity between Th17 and iTreg cells. PPARc regulates differentiation, activation and cytokine production, thereby controlling the induction of effector and regulatory responses, and is a promising therapeutic target for dysregulated immune responses and inflammation. Our modeling efforts predict that following PPARc activation, Th17 cells undergo phenotype switch and become iTreg cells. This prediction was validated by results of adoptive transfer studies showing an increase of colonic iTreg and a decrease of Th17 cells in the gut mucosa of mice with colitis following pharmacological activation of PPARc. Deletion of PPARc in CD4+ T cells impaired mucosal iTreg and enhanced colitogenic Th17 responses in mice with CD4+ T cell-induced colitis. Thus, for the first time we provide novel molecular evidence in vivo demonstrating that PPARc in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.en
dc.description.sponsorshipThis work was supported in part by a grant from the National Institutes of Health (5R01AT004308) to JBR, NIAID Contract No. HHSN272201000056C to JBR, and funds from the Nutritional Immunology and Molecular Medicine Laboratory (URL: The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.citationCarbo A, Hontecillas R, Kronsteiner B, Viladomiu M, Pedragosa M, et al. (2013) Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity. PLoS Comput Biol 9(4): e1003027. doi:10.1371/journal.pcbi.1003027en
dc.publisherPublic Library of Scienceen
dc.rightsIn Copyrighten
dc.subjectAdoptive transferen
dc.subjectCell differentiationen
dc.subjectRegulatory T cellsen
dc.subjectT cell receptorsen
dc.subjectT cellsen
dc.subjectTranscription factorsen
dc.titleSystems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticityen
dc.title.serialPLoS Computational Biologyen
dc.typeArticle - Refereeden


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