GFI1/HDAC1-axis differentially regulates immunosuppressive CD73 in human tumor-associated FOXP3+ Th17 and inflammation-linked Th17 cells

Eur J Immunol. 2021 May;51(5):1206-1217. doi: 10.1002/eji.202048892. Epub 2021 Feb 17.

Abstract

Plasticity between Th17 and Treg cells is regarded as a crucial determinant of tumor-associated immunosuppression. Classically Th17 cells mediate inflammatory responses through production of cytokine IL17. Recently, Th17 cells have also been shown to acquire suppressive phenotypes in tumor microenvironment. However, the mechanism by which they acquire such immunosuppressive properties is still elusive. Here, we report that in tumor microenvironment Th17 cell acquires immunosuppressive properties by expressing Treg lineage-specific transcription factor FOXP3 and ectonucleotidase CD73. We designate this cell as Th17reg cell and perceive that such immunosuppressive property is dependent on CD73. It was observed that in classical Th17 cell, GFI1 recruits HDAC1 to change the euchromatin into tightly-packed heterochromatin at the proximal-promoter region of CD73 to repress its expression. Whereas in Th17reg cells GFI1 cannot get access to CD73-promoter due to heterochromatin state at its binding site and, thus, cannot recruit HDAC1, failing to suppress the expression of CD73.

Keywords: CD73; FOXP3; GFI1; HDAC1; Th17.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase / metabolism
  • Cytokines / metabolism
  • DNA-Binding Proteins / metabolism*
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Histone Deacetylase 1 / metabolism*
  • Humans
  • Immunomodulation*
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Promoter Regions, Genetic
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism*
  • Transcription Factors / metabolism*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • Cytokines
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • GFI1 protein, human
  • Transcription Factors
  • 5'-Nucleotidase
  • HDAC1 protein, human
  • Histone Deacetylase 1