Journal
CELL REPORTS
Volume 37, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109796
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Funding
- National Institutes of Health [R01AI114442, R01CA237311, R01NS121249]
- American Lebanese Syrian Associated Charities (ALSAC)
- St. Jude
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The study found that IL-12 plays an important role in the priming of CD8 T cells, promoting TET2-mediated demethylation programming and influencing the expression of IFNg. This suggests that cytokines can guide the induction of epigenetically regulated traits in T cells.
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.
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