The epigenetic landscape of T cell exhaustion

Science. 2016 Dec 2;354(6316):1165-1169. doi: 10.1126/science.aae0491. Epub 2016 Oct 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cell Lineage / genetics
  • Chromatin / immunology
  • Chronic Disease
  • Disease Models, Animal
  • Enhancer Elements, Genetic*
  • Epigenesis, Genetic*
  • Gene Editing
  • HIV Infections / therapy
  • Hepatitis C, Chronic / therapy
  • Humans
  • Immunologic Memory / genetics*
  • Immunotherapy
  • Lymphocytic Choriomeningitis / therapy
  • Mice
  • Mice, Inbred C57BL
  • SOXB1 Transcription Factors / metabolism
  • T-Box Domain Proteins / metabolism
  • Transcription, Genetic


  • B7-H1 Antigen
  • Chromatin
  • SOXB1 Transcription Factors
  • T-Box Domain Proteins
  • T-box transcription factor TBX21