Proinflammatory cytokines promote TET2-mediated DNA demethylation during CD8 T cell effector differentiation

Cell Rep. 2021 Oct 12;37(2):109796. doi: 10.1016/j.celrep.2021.109796.


To gain insight into the signaling determinants of effector-associated DNA methylation programming among CD8 T cells, we explore the role of interleukin (IL)-12 in the imprinting of IFNg expression during CD8 T cell priming. We observe that anti-CD3/CD28-mediated stimulation of human naive CD8 T cells is not sufficient to induce substantial demethylation of the IFNg promoter. However, anti-CD3/CD28 stimulation in the presence of the inflammatory cytokine, IL-12, results in stable demethylation of the IFNg locus that is commensurate with IFNg expression. IL-12-associated demethylation of the IFNg locus is coupled to cell division through TET2-dependent demethylation in an ex vivo human chimeric antigen receptor T cell model system and an in vivo immunologically competent murine system. Collectively, these data illustrate that IL-12 signaling promotes TET2-mediated effector DNA demethylation programming in CD8 T cells and serve as proof of concept that cytokines can guide induction of epigenetically regulated traits for T cell-based immunotherapies.

Keywords: cytokines; effector CD8 T cells; epigenetics; inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • DNA Methylation / drug effects*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases / genetics
  • Dioxygenases / metabolism*
  • Disease Models, Animal
  • Humans
  • Immunologic Memory / drug effects
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism*
  • Interleukin-12 / pharmacology*
  • Lymphocytic Choriomeningitis / enzymology*
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / pathogenicity
  • Memory T Cells / drug effects*
  • Memory T Cells / enzymology
  • Memory T Cells / immunology
  • Memory T Cells / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proof of Concept Study
  • Signal Transduction


  • DNA-Binding Proteins
  • IFNG protein, human
  • IFNG protein, mouse
  • Interleukin-12
  • Interferon-gamma
  • Dioxygenases
  • TET2 protein, human
  • Tet2 protein, mouse