The epigenetic landscape of T cell exhaustion.

Sen, DR; Kaminski, J; Barnitz, RA; Kurachi, M; Gerdemann, U; Yates, KB; Tsao, H; Godec, J; LaFleur, MW; Brown, FD; +9 more...Tonnerre, P; Chung, RT; Tully, DCORCID logo; Allen, TM; Frahm, N; Lauer, GM; Wherry, EJ; Yosef, N; Haining, WN and (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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