title: Foxo1 Is a T Cell-Intrinsic Inhibitor of the RORγt-Th17 Program.
abstract: An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell-intrinsic manner.
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lainé
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Martin
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Luka
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Mir
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Auffray
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Lucas
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Bismuth
authors.affiliation: INSERM U1016, Institut Cochin, 75014 Paris, France;Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, 75014 Paris, France; andUniversité Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France celine.charvet@inserm.fr.
authors.forename: Céline
authors.initials: C
authors.lastname: Charvet
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt