Stat3 and Gfi-1 Transcription Factors Control Th17 Cell Immunosuppressive Activity via the Regulation of Ectonucleotidase Expression

Immunity. 2012 Mar 23;36(3):362-73. doi: 10.1016/j.immuni.2011.12.019. Epub 2012 Mar 8.

Abstract

Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4(+) and CD8(+) T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / genetics*
  • Animals
  • Antigens, CD / genetics*
  • Apyrase / genetics*
  • Binding Sites / genetics
  • DNA-Binding Proteins / immunology*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation
  • Interleukin-6 / pharmacology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • RNA, Small Interfering / genetics
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology*
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Th17 Cells / drug effects
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism*
  • Transcription Factors / immunology*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / pharmacology

Substances

  • Antigens, CD
  • DNA-Binding Proteins
  • Gfi1 protein, mouse
  • Interleukin-6
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factors
  • Transforming Growth Factor beta
  • 5'-Nucleotidase
  • Apyrase
  • CD39 antigen