title: The epigenetic landscape of T cell exhaustion.
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.
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors: Debattama R
authors: DR
authors: Sen
authors: Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: James
authors: J
authors: Kaminski
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: R Anthony
authors: RA
authors: Barnitz
authors: Institute of Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA.|Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Makoto
authors: M
authors: Kurachi
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Ulrike
authors: U
authors: Gerdemann
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Kathleen B
authors: KB
authors: Yates
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Hsiao-Wei
authors: HW
authors: Tsao
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors: Jernej
authors: J
authors: Godec
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors: Martin W
authors: MW
authors: LaFleur
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors: Flavian D
authors: FD
authors: Brown
authors: Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Pierre
authors: P
authors: Tonnerre
authors: Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Raymond T
authors: RT
authors: Chung
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139, USA.
authors: Damien C
authors: DC
authors: Tully
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139, USA.
authors: Todd M
authors: TM
authors: Allen
authors: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors: Nicole
authors: N
authors: Frahm
authors: Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Georg M
authors: GM
authors: Lauer
authors: Institute of Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA.|Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: E John
authors: EJ
authors: Wherry
authors: Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA. niryosef@berkeley.edu nicholas_haining@dfci.harvard.edu.|Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139, USA.|Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Nir
authors: N
authors: Yosef
authors: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. niryosef@berkeley.edu nicholas_haining@dfci.harvard.edu.|Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, MA 02115, USA.|Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors: W Nicholas
authors: WN
authors: Haining
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D019070:Cell Lineage / Q000235:genetics; D002843:Chromatin / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D000072669:Gene Editing; D015658:HIV Infections / Q000628:therapy; D019698:Hepatitis C, Chronic / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics*; D007167:Immunotherapy; D008216:Lymphocytic Choriomeningitis / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D060890:B7-H1 Antigen; D002843:Chromatin; D055748:SOXB1 Transcription Factors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor