Araki Yasuto, Fann Monchou, Wersto Robert, Weng Nan-Ping
Laboratory of Immunology and Flow Cytometry Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
J Immunol. 2008 Jun 15;180(12):8102-8. doi: 10.4049/jimmunol.180.12.8102.
To understand the mechanism regulating the effector function of memory CD8 T cells, we examined expression and chromatin state of a key transcription factor (eomesodermin, EOMES) and two of its targets: perforin (PRF1) and granzyme B (GZMB). Accessible chromatin associated histone 3 lysine 9 acetylation (H3K9Ac) was found significantly higher at the proximal promoter and the first exon region of all three genes in memory CD8 T cells than in naive CD8 T cells. Correspondingly, EOMES and PRF1 were constitutively higher expressed in memory CD8 T cells than in naive CD8 T cells at resting and activated states. In contrast, higher expression of GZMB was induced in memory CD8 T cells than in naive CD8 T cells only after activation. Regardless of their constitutive or inducible expression, decreased H3K9Ac levels after treatment with a histone acetyltransferase inhibitor (Curcumin) led to decreased expression of all three genes in activated memory CD8 T cells. These findings suggest that H3K9Ac associated accessible chromatin state serves as a corner stone for the differentially high expression of these effector genes in memory CD8 T cells. Thus, epigenetic changes mediated via histone acetylation may provide a chromatin "memory" for the rapid and robust transcriptional response of memory CD8 T cells.
为了解调节记忆性CD8 T细胞效应功能的机制，我们检测了关键转录因子（胚中胚层决定因子，EOMES）及其两个靶基因：穿孔素（PRF1）和颗粒酶B（GZMB）的表达及染色质状态。我们发现，与可及染色质相关的组蛋白3赖氨酸9乙酰化（H3K9Ac）在记忆性CD8 T细胞中，于所有这三个基因的近端启动子和第一个外显子区域的水平显著高于初始CD8 T细胞。相应地，在静息和活化状态下，记忆性CD8 T细胞中EOMES和PRF1的组成性表达均高于初始CD8 T细胞。相比之下，仅在活化后，记忆性CD8 T细胞中GZMB的表达诱导水平才高于初始CD8 T细胞。无论其组成性或诱导性表达如何，在用组蛋白乙酰转移酶抑制剂（姜黄素）处理后，H3K9Ac水平降低导致活化的记忆性CD8 T细胞中所有这三个基因的表达均下降。这些发现表明，与H3K9Ac相关的可及染色质状态是记忆性CD8 T细胞中这些效应基因差异高表达的基石。因此，通过组蛋白乙酰化介导的表观遗传变化可能为记忆性CD8 T细胞的快速且强烈的转录反应提供一种染色质“记忆”。
