1. The epigenetic landscape of T cell exhaustion
- Author
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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, and Haining, W Nicholas
- Subjects
Genetics ,Infectious Diseases ,Prevention ,Human Genome ,1.1 Normal biological development and functioning ,Underpinning research ,Infection ,Animals ,B7-H1 Antigen ,CD8-Positive T-Lymphocytes ,Cell Lineage ,Chromatin ,Chronic Disease ,Disease Models ,Animal ,Enhancer Elements ,Genetic ,Epigenesis ,Genetic ,Gene Editing ,HIV Infections ,Hepatitis C ,Chronic ,Humans ,Immunologic Memory ,Immunotherapy ,Lymphocytic Choriomeningitis ,Mice ,Mice ,Inbred C57BL ,SOXB1 Transcription Factors ,T-Box Domain Proteins ,Transcription ,Genetic ,General Science & Technology - Abstract
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.
- Published
- 2016