TGF-β-induced phosphorylation of Akt and Foxo transcription factors negatively regulates induced regulatory T cell differentiation

Yutaka Kurebayashi; Yukiko Baba; Akiko Minowa; Niken Adiba Nadya; Miyuki Azuma; Akihiko Yoshimura; Shigeo Koyasu; Shigenori Nagai

doi:10.1016/j.bbrc.2016.09.153

TGF-β-induced phosphorylation of Akt and Foxo transcription factors negatively regulates induced regulatory T cell differentiation

Biochem Biophys Res Commun. 2016 Nov 4;480(1):114-119. doi: 10.1016/j.bbrc.2016.09.153. Epub 2016 Oct 1.

Authors

Yutaka Kurebayashi¹, Yukiko Baba², Akiko Minowa², Niken Adiba Nadya³, Miyuki Azuma³, Akihiko Yoshimura⁴, Shigeo Koyasu⁵, Shigenori Nagai⁶

Affiliations

¹ 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.
² Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
³ Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan.
⁴ 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.
⁵ 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.
⁶ 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.

PMID: 27697523
DOI: 10.1016/j.bbrc.2016.09.153

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 I_A PI3K-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.

Keywords: Akt; Foxo; PI3K; TGF-β; Treg.

MeSH terms

Animals
CD4-Positive T-Lymphocytes / drug effects
CD4-Positive T-Lymphocytes / metabolism
Cell Differentiation / drug effects
Cell Differentiation / physiology
Class Ia Phosphatidylinositol 3-Kinase / genetics
Class Ia Phosphatidylinositol 3-Kinase / metabolism
Forkhead Box Protein O1 / metabolism*
Forkhead Box Protein O3 / metabolism
Forkhead Transcription Factors / metabolism
MAP Kinase Kinase Kinases / metabolism
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Mutant Strains
Mice, Transgenic
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Serine / metabolism
T-Lymphocytes, Regulatory / cytology*
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / metabolism
Transforming Growth Factor beta / metabolism
Transforming Growth Factor beta / pharmacology*

Substances

Forkhead Box Protein O1
Forkhead Box Protein O3
Forkhead Transcription Factors
FoxO3 protein, mouse
Foxo1 protein, mouse
Transforming Growth Factor beta
Serine
integrin-linked kinase
Class Ia Phosphatidylinositol 3-Kinase
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7