Abdelsamed Hossam A, Moustaki Ardiana, Fan Yiping, Dogra Pranay, Ghoneim Hazem E, Zebley Caitlin C, Triplett Brandon M, Sekaly Rafick-Pierre, Youngblood Ben
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
J Exp Med. 2017 Jun 5;214(6):1593-1606. doi: 10.1084/jem.20161760. Epub 2017 May 10.
Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell-mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (T), and longer-lived central memory (T) and stem cell memory (T) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7- and IL-15-mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of T and T memory cells resulted in phenotypic conversion into T cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired T-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.
记忆性CD8 T细胞的抗原非依赖性稳态对于维持长期的T细胞介导的免疫至关重要。在本研究中，我们报告了在体外和体内稳态增殖过程中，人类记忆性CD8 T细胞效应潜能的维持与获得性DNA甲基化程序的保存相关联。对原代人类初始、短期效应记忆（T）、长期中央记忆（T）和干细胞记忆（T）CD8 T细胞进行全基因组亚硫酸氢盐测序，鉴定出启动子去甲基化且易于表达的效应分子。在IL-7和IL-15介导的体外细胞增殖过程中，效应位点的去甲基化得以遗传保存。相反，细胞因子驱动的T和T记忆细胞增殖导致其表型转化为T细胞，并与CCR7和Tcf7位点甲基化增加相关联。此外，在淋巴细胞清除的受体中进行体内增殖的单倍体相合供体记忆性CD8 T细胞也维持其效应相关的去甲基化状态，但获得了T相关程序。这些数据表明，在细胞因子驱动的人类记忆性CD8 T细胞亚群相互转化过程中，效应相关的表观遗传程序得以保存。
