title: TGF-β-induced phosphorylation of Akt and Foxo transcription factors negatively regulates induced regulatory T cell differentiation.
abstract: Transforming growth factor-β (TGF-β) is a pivotal cytokine in the differentiation of regulatory T cells, and Foxo transcription factors positively regulate this process. On the other hand, the function of Foxo transcription factors is negatively regulated by PI3K/Akt signaling, which is activated by TGF-β in many types of cells; yet the role of TGF-β in Akt activity and its downstream substrates in CD4+T cells, including Foxo transcription factors, remains to be determined. Herein, we demonstrate that TGF-β selectively induces Akt phosphorylation at Ser473 but not at Thr308 in a class IAPI3K-dependent manner in CD4+T cells, resulting in the phosphorylation and inhibition of Foxo transcription factors and negatively regulating the differentiation of induced regulatory T cells (iTregs). These observations reveal a novel negative regulatory mechanism involving Akt and Foxo transcription factors induced by TGF-β in the iTreg differentiation process.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kurebayashi
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Minowa
authors.affiliation: Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Niken Adiba
authors.initials: NA
authors.lastname: Nadya
authors.affiliation: Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology (JST), Tokyo 102-0075, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Laboratory for Immune Cell System, RCAI, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan; Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan. Electronic address: nagai.mim@tmd.ac.jp.
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nagai
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D000099200:Scaffold Protein ILK; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D020930:MAP Kinase Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D016212:Transforming Growth Factor beta; D000099200:Scaffold Protein ILK; D000099151:MAP Kinase Kinase Kinase 7; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse
keywords: Akt; Foxo; PI3K; TGF-β; Treg