The epigenetic landscape of T cell exhaustion.

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; +9 more...Tonnerre, Pierre; Chung, Raymond T; Tully, Damien CORCID logo; Allen, Todd M; Frahm, Nicole; Lauer, Georg M; Wherry, E John; Yosef, Nir; and Haining, W Nicholas (2016) The epigenetic landscape of T cell exhaustion. SCIENCE, 354 (6316). pp. 1165-1169. ISSN 0036-8075 DOI: 10.1126/science.aae0491
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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.


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