转化生长因子-β诱导的Akt和Foxo转录因子磷酸化对诱导性调节性T细胞分化起负向调节作用。

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

作者信息

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

机构信息

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.

Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.

出版信息

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

DOI:10.1016/j.bbrc.2016.09.153

PMID:27697523

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 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.

摘要

转化生长因子-β（TGF-β）是调节性T细胞分化中的关键细胞因子，而Foxo转录因子正向调节这一过程。另一方面，Foxo转录因子的功能受到PI3K/Akt信号通路的负调控，在许多类型的细胞中该信号通路由TGF-β激活；然而，TGF-β在CD4 T细胞中Akt活性及其下游底物（包括Foxo转录因子）中的作用仍有待确定。在此，我们证明TGF-β以I类PI3K依赖性方式在CD4 T细胞中选择性诱导Akt在Ser473位点而非Thr308位点磷酸化，并导致Foxo转录因子磷酸化和抑制，从而负向调节诱导性调节性T细胞（iTregs）的分化。这些观察结果揭示了TGF-β在iTreg分化过程中诱导的涉及Akt和Foxo转录因子的新型负调控机制。