The epigenetic landscape of T cell exhaustion

  • Science. 2016 Dec 2;354(6316):1165-1169. doi: 10.1126/science.aae0491.
Debattama R Sen  1  2 ,  James Kaminski  3 ,  R Anthony Barnitz  1 ,  Makoto Kurachi  4  5 ,  Ulrike Gerdemann  1 ,  Kathleen B Yates  1 ,  Hsiao-Wei Tsao  1 ,  Jernej Godec  1  2 ,  Martin W LaFleur  1  2 ,  Flavian D Brown  1  2 ,  Pierre Tonnerre  6 ,  Raymond T Chung  6 ,  Damien C Tully  7 ,  Todd M Allen  7 ,  Nicole Frahm  8 ,  Georg M Lauer  6 ,  E John Wherry  4  5 ,  Nir Yosef  9  7  10 ,  W Nicholas Haining  11  12  13
Affiliations
  • 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. [email protected] [email protected].
  • 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. [email protected] [email protected].
  • 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.
PMID: 27789799 DOI: 10.1126/science.aae0491
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.