Sen Debattama R, Kaminski James, Barnitz R Anthony, Kurachi Makoto, Gerdemann Ulrike, Yates Kathleen B, Tsao Hsiao-Wei, Godec Jernej, LaFleur Martin W, Brown Flavian D, Tonnerre Pierre, Chung Raymond T, Tully Damien C, Allen Todd M, Frahm Nicole, Lauer Georg M, Wherry E John, Yosef Nir, Haining W Nicholas
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Science. 2016 Dec 2;354(6316):1165-1169. doi: 10.1126/science.aae0491. Epub 2016 Oct 27.
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.
癌症和慢性病毒感染中耗竭的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，对耗竭T细胞中基因表达的调控了解甚少。在这里，我们定义了耗竭的CD8 T细胞中可及的染色质景观，并表明它与功能性记忆CD8 T细胞不同。人类和慢性病毒感染小鼠模型中的耗竭CD8 T细胞获得了一种状态特异性的表观遗传景观，该景观被组织成增强子的功能模块。基因组编辑表明，PD-1的表达部分受一个耗竭特异性增强子的调控，该增强子包含必需的视黄酸受体（RAR）、T-bet和Sox3基序。功能性增强子图谱可能为基因组编辑提供靶点，从而优先改变耗竭CD8 T细胞中的基因表达。
