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Science. 2016 Dec 2;354(6316):1165-1169. Epub 2016 Oct 27.

The epigenetic landscape of T cell exhaustion.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
2
Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
3
Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
4
Institute of Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA.
5
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
6
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
7
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139, USA.
8
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
9
Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. niryosef@berkeley.edu nicholas_haining@dfci.harvard.edu.
10
Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA.
11
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. niryosef@berkeley.edu nicholas_haining@dfci.harvard.edu.
12
Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, MA 02115, USA.
13
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.

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.

PMID:
27789799
PMCID:
PMC5497589
DOI:
10.1126/science.aae0491
[Indexed for MEDLINE]
Free PMC Article

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