Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity
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{"title"=>"Systems Modeling of Molecular Mechanisms Controlling Cytokine-driven CD4+ T Cell Differentiation and Phenotype Plasticity", "type"=>"journal", "authors"=>[{"first_name"=>"Adria", "last_name"=>"Carbo", "scopus_author_id"=>"36637003700"}, {"first_name"=>"Raquel", "last_name"=>"Hontecillas", "scopus_author_id"=>"6602639316"}, {"first_name"=>"Barbara", "last_name"=>"Kronsteiner", "scopus_author_id"=>"17135052500"}, {"first_name"=>"Monica", "last_name"=>"Viladomiu", "scopus_author_id"=>"42962600000"}, {"first_name"=>"Mireia", "last_name"=>"Pedragosa", "scopus_author_id"=>"55017879700"}, {"first_name"=>"Pinyi", "last_name"=>"Lu", "scopus_author_id"=>"37037727900"}, {"first_name"=>"Casandra W.", "last_name"=>"Philipson", "scopus_author_id"=>"55613529300"}, {"first_name"=>"Stefan", "last_name"=>"Hoops", "scopus_author_id"=>"15128967000"}, {"first_name"=>"Madhav", "last_name"=>"Marathe", "scopus_author_id"=>"7005103606"}, {"first_name"=>"Stephen", "last_name"=>"Eubank", "scopus_author_id"=>"6602912192"}, {"first_name"=>"Keith", "last_name"=>"Bisset", "scopus_author_id"=>"6701651050"}, {"first_name"=>"Katherine", "last_name"=>"Wendelsdorf", "scopus_author_id"=>"26025382700"}, {"first_name"=>"Abdul", "last_name"=>"Jarrah", "scopus_author_id"=>"8204801800"}, {"first_name"=>"Yongguo", "last_name"=>"Mei", "scopus_author_id"=>"55369974500"}, {"first_name"=>"Josep", "last_name"=>"Bassaganya-Riera", "scopus_author_id"=>"6603033549"}], "year"=>2013, "source"=>"PLoS Computational Biology", "identifiers"=>{"pmid"=>"23592971", "issn"=>"1553734X", "sgr"=>"84876915404", "pui"=>"368832132", "scopus"=>"2-s2.0-84876915404", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "doi"=>"10.1371/journal.pcbi.1003027"}, "id"=>"b02879fe-c0d6-384b-ba6a-f1e8cb322974", "abstract"=>"Differentiation 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 (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ 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 PPARγ 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 PPARγ. Deletion of PPARγ 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 PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.", "link"=>"http://www.mendeley.com/research/systems-modeling-molecular-mechanisms-controlling-cytokinedriven-cd4-t-cell-differentiation-phenotyp-2", "reader_count"=>85, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>5, "Researcher"=>20, "Student > Doctoral Student"=>2, "Student > Ph. D. 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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1015563", "https://ndownloader.figshare.com/files/1015564", "https://ndownloader.figshare.com/files/1015565", "https://ndownloader.figshare.com/files/1015567", "https://ndownloader.figshare.com/files/1015569", "https://ndownloader.figshare.com/files/1015570", "https://ndownloader.figshare.com/files/1015571", "https://ndownloader.figshare.com/files/1015572", "https://ndownloader.figshare.com/files/1015573", "https://ndownloader.figshare.com/files/1015574", "https://ndownloader.figshare.com/files/1015575", "https://ndownloader.figshare.com/files/1015576", "https://ndownloader.figshare.com/files/1015577", "https://ndownloader.figshare.com/files/1015578", "https://ndownloader.figshare.com/files/1015579", "https://ndownloader.figshare.com/files/1015580", "https://ndownloader.figshare.com/files/1015581", "https://ndownloader.figshare.com/files/1015582", "https://ndownloader.figshare.com/files/1015583", "https://ndownloader.figshare.com/files/1015584", "https://ndownloader.figshare.com/files/1015585"], "description"=>"<div><p>Differentiation 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 (PPARγ) in modulating plasticity between Th17 and iTreg cells. PPARγ 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 PPARγ 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 PPARγ. Deletion of PPARγ 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 <i>in vivo</i> demonstrating that PPARγ in addition to regulating CD4+ T cell differentiation also plays a major role controlling Th17 and iTreg plasticity in the gut mucosa.</p></div>", "links"=>[], "tags"=>["immunology", "Immune cells", "t cells", "immunity", "Adaptive immunity", "immunoregulation", "immunomodulation", "Computer modeling", "Gastroenterology and hepatology", "Inflammatory bowel disease", "modeling", "molecular", "mechanisms", "controlling", "cytokine-driven", "differentiation", "phenotype"], "article_id"=>675482, "categories"=>["Information And Computing Sciences", "Medicine", "Biological Sciences"], "users"=>["Adria Carbo", "Raquel Hontecillas", "Barbara Kronsteiner", "Monica Viladomiu", "Mireia Pedragosa", "Pinyi Lu", "Casandra W. 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  • {"files"=>["https://ndownloader.figshare.com/files/1015550"], "description"=>"<p>(A) Computational simulation of the effect of <i>in silico</i> activation of PPARγ in a T helper (Th)17 cell on the levels of FOXP3, IL-17 and RORγt. (B) PPARγ inhibits Th17 differentiation. Naïve wild-type CD4+ T cells differentiated with IL-6 in combination with TGF-β <i>in vitro</i> for 60h express less RORγt and produce lower levels of IL-17A when compared to T cell-specific PPARγ null Th17 cells. (C) Increasing concentrations of pioglitazone (PIO), a full PPARγ agonist, upregulate FOXP3 in wild-type Th17 differentiated cells following 24 h treatment and down-regulate RORγt and IL-17A in wild-type cells. (D) Increasing concentrations of PIO do not have an effect in PPARγ null Th17 cells. The double-positive region can be observed in the upper right part of the flow plots.</p>", "links"=>[], "tags"=>["immunology", "Immune cells", "t cells", "immunity", "Adaptive immunity", "immunoregulation", "immunomodulation", "Computer modeling", "Gastroenterology and hepatology", "Inflammatory bowel disease", "peroxisome", "proliferator-activated", "receptor", "regulates", "differentiation"], "article_id"=>675476, "categories"=>["Information And Computing Sciences", "Medicine", "Biological Sciences"], "users"=>["Adria Carbo", "Raquel Hontecillas", "Barbara Kronsteiner", "Monica Viladomiu", "Mireia Pedragosa", "Pinyi Lu", "Casandra W. Philipson", "Stefan Hoops", "Madhav Marathe", "Stephen Eubank", "Keith Bisset", "Katherine Wendelsdorf", "Abdul Jarrah", "Yongguo Mei", "Josep Bassaganya-Riera"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003027.g002", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_peroxisome_proliferator_activated_receptor_947_PPAR_947_regulates_differentiation_of_CD4_T_cells_/675476", "title"=>"Activation of peroxisome proliferator-activated receptor γ (PPARγ) regulates differentiation of CD4+ T cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:31:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1015557"], "description"=>"<p>(A) SCID recipients were administered either wild-type or PPARγ null naïve CD4+ T cells. Representative photomicrographs of colons from (A.A–A.D) non-transferred (A.B–A.E) wild-type recipient and (A.C,A.F) T cell-specific PPARγ null recipient mice. Original magnification 40 or 100×. (B) Disease activity scores of SCID recipient mice of wild-type or PPARγ null naïve CD4+ T cells. Data are represented as mean ± standard error. Points with an asterisk are significantly different when compared to the PBS-treated group (<i>P</i><0.05).</p>", "links"=>[], "tags"=>["immunology", "Immune cells", "t cells", "immunity", "Adaptive immunity", "immunoregulation", "immunomodulation", "Computer modeling", "Gastroenterology and hepatology", "Inflammatory bowel disease", "proliferator", "activated", "receptor", "gamma", "ameliorates", "colonic", "inflammation", "signs"], "article_id"=>675479, "categories"=>["Information And Computing Sciences", "Medicine", "Biological Sciences"], "users"=>["Adria Carbo", "Raquel Hontecillas", "Barbara Kronsteiner", "Monica Viladomiu", "Mireia Pedragosa", "Pinyi Lu", "Casandra W. Philipson", "Stefan Hoops", "Madhav Marathe", "Stephen Eubank", "Keith Bisset", "Katherine Wendelsdorf", "Abdul Jarrah", "Yongguo Mei", "Josep Bassaganya-Riera"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003027.g004", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Peroxisome_proliferator_activated_receptor_gamma_PPAR_947_ameliorates_colonic_inflammation_and_clinical_signs_of_disease_/675479", "title"=>"Peroxisome proliferator activated receptor gamma (PPARγ) ameliorates colonic inflammation and clinical signs of disease.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:31:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/1015561"], "description"=>"<p>(A) Computer simulation illustrating a down-modulation of IL-17, STAT3, RORγt and upregulation of FOXP3 in a differentiated Th17 cell following PPARγ activation. (B) Combination of time-course and PPARγ concentration scan to assess changes of IL-17, STAT3, RORγt and FOXP3 over time. (C) Experimental design for the validation of the model prediction. (D–E) Accumulation of iTreg and Th17 cells in the mesenteric lymph nodes (MLN) and colonic lamina propria (LP) of recipient mice.</p>", "links"=>[], "tags"=>["immunology", "Immune cells", "t cells", "immunity", "Adaptive immunity", "immunoregulation", "immunomodulation", "Computer modeling", "Gastroenterology and hepatology", "Inflammatory bowel disease", "modeling", "peroxisome", "proliferator-activated", "receptor", "regulating", "plasticity", "helper", "17", "induced", "cells"], "article_id"=>675480, "categories"=>["Information And Computing Sciences", "Medicine", "Biological Sciences"], "users"=>["Adria Carbo", "Raquel Hontecillas", "Barbara Kronsteiner", "Monica Viladomiu", "Mireia Pedragosa", "Pinyi Lu", "Casandra W. Philipson", "Stefan Hoops", "Madhav Marathe", "Stephen Eubank", "Keith Bisset", "Katherine Wendelsdorf", "Abdul Jarrah", "Yongguo Mei", "Josep Bassaganya-Riera"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003027.g005", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Validation_of_the_modeling_prediction_regarding_the_role_of_peroxisome_proliferator_activated_receptor_PPAR_947_in_regulating_the_plasticity_between_T_helper_Th_17_and_induced_regulatory_T_cells_iTreg_/675480", "title"=>"Validation of the modeling prediction regarding the role of peroxisome proliferator-activated receptor (PPAR) γ in regulating the plasticity between T helper (Th) 17 and induced regulatory T cells (iTreg).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:31:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/1015552"], "description"=>"<p>(A–D) Computational simulation of the effect of PPARγ deficiency on differentiation from a naïve state into either Th17 or iTreg phenotypes. (E) Th17 cell accumulation in spleens of recipients of wild-type versus PPARγ null CD4+ T cells. (F) Treg cell accumulation in spleen, mesenteric lymph nodes (MLN) and lamina propria (LP) of SCID recipient mice.</p>", "links"=>[], "tags"=>["immunology", "Immune cells", "t cells", "immunity", "Adaptive immunity", "immunoregulation", "immunomodulation", "Computer modeling", "Gastroenterology and hepatology", "Inflammatory bowel disease", "proliferator-activated", "receptor", "suppresses", "helper", "differentiation", "upregulates", "foxp3"], "article_id"=>675478, "categories"=>["Information And Computing Sciences", "Medicine", "Biological Sciences"], "users"=>["Adria Carbo", "Raquel Hontecillas", "Barbara Kronsteiner", "Monica Viladomiu", "Mireia Pedragosa", "Pinyi Lu", "Casandra W. Philipson", "Stefan Hoops", "Madhav Marathe", "Stephen Eubank", "Keith Bisset", "Katherine Wendelsdorf", "Abdul Jarrah", "Yongguo Mei", "Josep Bassaganya-Riera"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003027.g003", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Peroxisome_proliferator_activated_receptor_PPAR_suppresses_T_helper_Th_17_cell_differentiation_and_upregulates_FOXP3_expression_in_vivo_/675478", "title"=>"Peroxisome proliferator-activated receptor (PPAR) γ suppresses T helper (Th)17 cell differentiation and upregulates FOXP3 expression <i>in vivo</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:31:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/1015549"], "description"=>"<p>The signaling network illustrates network topologies associated with differentiation towards T helper (Th)1 (red shadow), Th2 (green shadow), Th17 (blue shadow) and induced regulatory T cells (iTreg, yellow shadow). The network is provided in Systems Biology Markup Language-compliant format.</p>", "links"=>[], "tags"=>["immunology", "Immune cells", "t cells", "immunity", "Adaptive immunity", "immunoregulation", "immunomodulation", "Computer modeling", "Gastroenterology and hepatology", "Inflammatory bowel disease", "illustrating", "intracellular", "pathways", "transcriptional", "controlling", "differentiation"], "article_id"=>675475, "categories"=>["Information And Computing Sciences", "Medicine", "Biological Sciences"], "users"=>["Adria Carbo", "Raquel Hontecillas", "Barbara Kronsteiner", "Monica Viladomiu", "Mireia Pedragosa", "Pinyi Lu", "Casandra W. Philipson", "Stefan Hoops", "Madhav Marathe", "Stephen Eubank", "Keith Bisset", "Katherine Wendelsdorf", "Abdul Jarrah", "Yongguo Mei", "Josep Bassaganya-Riera"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1003027.g001", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Network_model_illustrating_the_complex_intracellular_signaling_pathways_and_transcriptional_factors_controlling_the_CD4_T_cell_differentiation_process_/675475", "title"=>"Network model illustrating the complex intracellular signaling pathways and transcriptional factors controlling the CD4+ T cell differentiation process.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-04-04 01:31:15"}

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Relative Metric

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