TNF-α enhances Th9 cell differentiation and antitumor immunity via TNFR2-dependent pathways

Yuxue Jiang, Jintong Chen, Enguang Bi, Yinghua Zhao, Tianxue Qin, Yiming Wang, Alison Wang, Sujun Gao, Qing Yi, Siqing Wang

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Tumor specific Th9 cells are potential effector cells for adoptive therapy of human cancers. TNF family members OX40L, TL1A and GITRL have been shown to promote the induction of Th9 cells and antitumor immunity. However, the role of TNF-α, the prototype of the TNF superfamily cytokines, in Th9 cell differentiation and their antitumor efficacy is not defined. Here, we showed that TNF-α potently promoted naïve CD4 + T cells to differentiate into Th9 cells in vitro. Furthermore, the addition of TNF-α during Th9 cell differentiation increased T cell survival and proliferation. More importantly, the adoptive transfer of TNF-α-treated Th9 cells induced more potent antitumor effects than regular Th9 cells in mouse tumor model. TNF-α signals via two cell surface receptors, TNFR1 and TNFR2. Mechanistic studies revealed that TNF-α drove Th9 cell differentiation through TNFR2 but not TNFR1. In addition, under Th9 polarizing condition, TNF-α activated STAT5 and NF-κB pathways in T cells in a TNFR2-dependent manner. Inhibition of STAT5 and NF-κB pathways by their specific inhibitors impaired TNF-α-induced Th9 cell differentiation. Our results identified TNF-α as a new powerful inducer of Th9 cells and clarified the molecular mechanisms underlying TNF-α-induced Th9 cell differentiation.

Original languageEnglish (US)
Article number28
JournalJournal for immunotherapy of cancer
Issue number1
StatePublished - Feb 4 2019


  • STAT5
  • TNF-α
  • TNFR2
  • Th9

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research


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