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

• DOI: 10.1016/j.celrep.2021.109796
• Publication Date: 2021-10-13T14:13:30Z
• Authors: Caitlin C. Zebley; Hossam A. Abdelsamed; Hazem E. Ghoneim; Shanta Alli; Charmaine Brown; Dalia Haydar; Tian Mi; Tarsha Harris; Maureen A. McGargill; Giedre Krenciute; Ben Youngblood
• Keywords: Mice, Knockout; 0303 health sciences; Cell Differentiation; CD8-Positive T-Lymphocytes; DNA Methylation; Lymphocytic Choriomeningitis; Interleukin-12; Proof of Concept Study; Article; Dioxygenases; DNA-Binding Proteins; Mice, Inbred C57BL; Disease Models, Animal; Interferon-gamma; Memory T Cells; 03 medical and health sciences; Animals; Humans; Lymphocytic choriomeningitis virus; Immunologic Memory; Cells, Cultured; Cell Proliferation; Signal Transduction

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.