Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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.
为了深入了解 CD8 T 细胞中效应相关 DNA 甲基化编程的信号决定因素，我们探讨了白细胞介素 (IL)-12 在 CD8 T 细胞初始激活期间 IFNγ表达印迹中的作用。我们观察到，抗 CD3/CD28 介导的人幼稚 CD8 T 细胞刺激不足以诱导 IFNγ启动子的大量去甲基化。然而，在炎症细胞因子 IL-12 的存在下，抗 CD3/CD28 刺激导致 IFNγ基因座的稳定去甲基化，与 IFNγ表达相当。通过体外嵌合抗原受体 T 细胞模型系统和体内免疫功能健全的鼠系统中的 TET2 依赖性去甲基化，IL-12 相关的 IFNγ基因座去甲基化与细胞分裂偶联。总之，这些数据表明，IL-12 信号促进了 CD8 T 细胞中 TET2 介导的效应 DNA 去甲基化编程，并为细胞因子可以指导基于 T 细胞的免疫疗法中表观遗传调控特征的诱导提供了概念验证。
