The epigenetic landscape of T cell exhaustion.
The epigenetic landscape of T cell exhaustion.
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DOI：
10.1126/science.aae0491
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发表时间：
2016-12-02
期刊：
影响因子：
--
通讯作者：
Haining WN
中科院分区：
文献类型：
--
作者：
Sen DR;Kaminski J;Barnitz RA;Kurachi M;Gerdemann U;Yates KB;Tsao HW;Godec J;LaFleur MW;Brown FD;Tonnerre P;Chung RT;Tully DC;Allen TM;Frahm N;Lauer GM;Wherry EJ;Yosef N;Haining WN
癌症和慢性病毒感染中耗尽的T细胞表达独特的基因模式，包括程序性细胞死亡蛋白1（PD-1）的持续表达。然而，对耗尽的T细胞中基因表达的调控知之甚少。在这里，我们定义了耗尽的CD 8 + T细胞中可访问的染色质景观，并表明它与功能性记忆CD 8 + T细胞不同。人类和慢性病毒感染小鼠模型中耗尽的CD 8 + T细胞获得了组织成增强子功能模块的状态特异性表观遗传景观。基因组编辑表明，PD-1表达部分受到含有必需RAR、T-bet和Sox 3基序的耗竭特异性增强子的调控。功能增强子图谱可以为基因组编辑提供靶点，从而优先改变耗尽的CD 8 + T细胞中的基因表达。
Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells.