1. The epigenetic landscape of T cell exhaustion
- Author
-
Nir Yosef, W. Nicholas Haining, Debattama R. Sen, Damien C. Tully, Ulrike Gerdemann, Flavian D. Brown, Kathleen B. Yates, Pierre Tonnerre, James Kaminski, R. Anthony Barnitz, Nicole Frahm, Jernej Godec, Makoto Kurachi, Raymond T. Chung, Martin W. LaFleur, Georg M. Lauer, Todd M. Allen, Hsiao-Wei Tsao, and E. John Wherry
- Subjects
0301 basic medicine ,HIV Infections ,CD8-Positive T-Lymphocytes ,Inbred C57BL ,B7-H1 Antigen ,Mice ,0302 clinical medicine ,Gene expression ,Chronic ,Genetics ,Regulation of gene expression ,Gene Editing ,Multidisciplinary ,Hepatitis C ,Chromatin ,medicine.anatomical_structure ,Infectious Diseases ,030220 oncology & carcinogenesis ,Immunotherapy ,Infection ,Transcription ,Enhancer Elements ,General Science & Technology ,T cell ,1.1 Normal biological development and functioning ,Biology ,Lymphocytic Choriomeningitis ,complex mixtures ,Article ,03 medical and health sciences ,Genetic ,Underpinning research ,medicine ,Animals ,Humans ,Cell Lineage ,Epigenetics ,Enhancer ,Gene ,Animal ,SOXB1 Transcription Factors ,Prevention ,Human Genome ,030104 developmental biology ,Disease Models ,Chronic Disease ,T-Box Domain Proteins ,Immunologic Memory ,CD8 ,Epigenesis - 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