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PMID: 27789799 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The epigenetic landscape of T cell exhaustion.

Science (New York, N.Y.) ·Vol. 354 ·No. 6316 ·2016-00-02 ·Pages 1165-1169

Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, Tonnerre P, Chung RT, Tully DC, Allen TM, Frahm N, Lauer GM, Wherry EJ, Yosef N, Haining WN

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.

MeSH Terms
Animals B7-H1 Antigen/antagonists & inhibitors,genetics CD8-Positive T-Lymphocytes/immunology,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
Chemicals
B7-H1 Antigen Chromatin SOXB1 Transcription Factors T-Box Domain Proteins T-box transcription factor TBX21
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Sen Debattama R
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. | Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Kaminski James
Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Barnitz R Anthony
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Kurachi Makoto
Institute of Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA. | Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Gerdemann Ulrike
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Yates Kathleen B
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Tsao Hsiao-Wei
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Godec Jernej
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. | Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
LaFleur Martin W
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. | Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Brown Flavian D
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. | Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Tonnerre Pierre
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Chung Raymond T
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Tully Damien C
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139, USA.
Allen Todd M
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA 02139, USA.
Frahm Nicole
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Lauer Georg M
Gastrointestinal Unit and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
Wherry E John
Institute of Immunology, University of Pennsylvania, Philadelphia, PA 19104, USA. | Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Yosef Nir
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.
Haining W Nicholas
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.
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aae0491
Email
niryosef@berkeley.edu
nicholas_haining@dfci.harvard.edu
Published
2016-00-02
Epub
2016-00-27
Pages
1165-1169
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC5497589
Subset
IM
Grants
NIAID NIH HHS · R21 AI078809 · United States
NIDDK NIH HHS · P30 DK043351 · United States
NHGRI NIH HHS · U01 HG007910 · United States
NIMH NIH HHS · U01 MH105979 · United States
NIAID NIH HHS · R01 AI091493 · United States
NIAID NIH HHS · U19 AI082630 · United States
NIAID NIH HHS · UM1 AI068618 · United States
NIAID NIH HHS · R01 AI115712 · United States
Corrections
CommentIn
PMID: 27934723
CommentIn
PMID: 28225757
CommentIn
PMID: 28437384
External Links
PubMed source DOI: 10.1126/science.aae0491 PMC Full Text View journal details
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