Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7

Enguang Bi, Xingzhe Ma, Yong Lu, Maojie Yang, Qiang Wang, Gang Xue, Jianfei Qian, Siqing Wang, Qing Yi

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Tumor-specific CD4+ T helper 9 (TH9) cells, so-called because of their production of the cytokine interleukin-9 (IL-9), are a powerful effector T cell subset for cancer immunotherapy. We found that pretreatment of naïve CD4+ T cells with IL-7 further enhanced their differentiation into TH9 cells and augmented their antitumor activity. IL-7 markedly increased the abundance of the histone acetyltransferase p300 by activating the STAT5 and PI3K-AKT-mTOR signaling pathways and promoting the acetylation of histones at the Il9 promoter. As a result, the transcriptional regulator Foxo1 was dephosphorylated and translocated to the nucleus, bound to the Il9 promoter, and induced the production of IL-9 protein. In contrast, Foxp1, which bound to the Il9 promoter in naïve CD4+ T cells and inhibited Il9 expression, was outcompeted for binding to the Il9 promoter by Foxo1 and translocated to the cytoplasm. Furthermore, forced expression of Foxo1 or a deficiency in Foxp1 in CD4+ T cells markedly increased the production of IL-9, whereas a deficiency in Foxo1 inhibited the ability of IL-7 to enhance the differentiation and antitumor activity of TH9 cells. Thus, we identified the roles of Foxo1 as a positive regulator and Foxp1 as a negative regulator of TH9 cell differentiation and antitumor activity, which may provide potential targets for cancer immunotherapy.

Original languageEnglish (US)
JournalScience signaling
Volume10
Issue number500
DOIs
StatePublished - Oct 10 2017

Keywords

  • Acetylation
  • Animals
  • CD4-Positive T-Lymphocytes/drug effects
  • Cell Differentiation/drug effects
  • Cells, Cultured
  • Cytokines/metabolism
  • Forkhead Box Protein O1/physiology
  • Forkhead Transcription Factors/physiology
  • Gene Expression Regulation
  • Histones/metabolism
  • Humans
  • Interleukin-7/pharmacology
  • Interleukin-9/genetics
  • Lung Neoplasms/immunology
  • Lymphocyte Activation
  • Melanoma/immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Repressor Proteins/physiology
  • Signal Transduction
  • T-Lymphocytes, Helper-Inducer/drug effects

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