title: Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes.
abstract: The transcription factor Foxo3 plays a crucial role in myeloid cell function but its role in lymphoid cells remains poorly defined. Here, we have shown that Foxo3 expression was increased after T cell receptor engagement and played a specific role in the polarization of CD4+T cells toward pathogenic T helper 1 (Th1) cells producing interferon-γ (IFN-γ) and granulocyte monocyte colony stimulating factor (GM-CSF). Consequently, Foxo3-deficient mice exhibited reduced susceptibility to experimental autoimmune encephalomyelitis. At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+T cells restored both IFN-γ and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Stienne
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Michaël F
authors.initials: MF
authors.lastname: Michieletto
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Benamar
authors.affiliation: UGM 4127, Oncopole, Toulouse 31059, France.
authors.forename: Nadège
authors.initials: N
authors.lastname: Carrié
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Xuan-Hung
authors.initials: XH
authors.lastname: Nguyen
authors.affiliation: Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse 31024, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Lippi
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Duguet
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
authors.affiliation: Molecular Biology Section, Division of Biological Sciences and Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0377, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France.
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
authors.affiliation: UMR Inserm, U1043, Toulouse 31300, France; UMR CNRS, U5282, Toulouse 31300, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse 31300, France. Electronic address: anne.dejean@inserm.fr.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Dejean
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C491198:Eomes protein, mouse; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D007375:Interleukin-1; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: CD4 T cell differentiation; EAE; Eomes; GM-CSF; IFN-γ; T-bet; autoimmunity; pathogenic Th1; transcription factors