The epigenetic landscape of T cell exhaustion

被引：812

作者：

Sen, Debattama R. ^{[1
,2
]}

Kaminski, James ^{[3
]}

Barnitz, R. Anthony ^{[1
]}

Kurachi, Makoto ^{[4
,5
]}

Gerdemann, Ulrike ^{[1
]}

Yates, Kathleen B. ^{[1
]}

Tsao, Hsiao-Wei ^{[1
]}

Godec, Jernej ^{[1
,2
]}

LaFleur, Martin W. ^{[1
,2
]}

Brown, Flavian D. ^{[1
,2
]}

Tonnerre, Pierre ^{[6
,7
]}

Chung, Raymond T. ^{[6
,7
]}

Tully, Damien C. ^{[8
,9
]}

Allen, Todd M. ^{[8
,9
]}

Frahm, Nicole ^{[10
]}

Lauer, Georg M. ^{[6
,7
]}

Wherry, E. John ^{[4
,5
]}

Yosef, Nir ^{[3
,8
,9
,11
]}

Haining, W. Nicholas ^{[1
,12
,13
]}

机构：

[1] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

[2] Harvard Med Sch, Div Med Sci, Boston, MA 02115 USA

[3] Univ Calif Berkeley, Ctr Computat Biol, Berkeley, CA 94720 USA

[4] Univ Penn, Inst Immunol, Philadelphia, PA 19104 USA

[5] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA

[6] Harvard Med Sch, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02115 USA

[7] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Liver, Boston, MA 02115 USA

[8] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02139 USA

[9] Harvard Univ, Boston, MA 02139 USA

[10] Fred Hutchinson Canc Res Ctr, Vaccine & Infect Dis Div, Seattle, WA 98109 USA

[11] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA

[12] Childrens Hosp, Div Pediat Hematol & Oncol, Boston, MA 02115 USA

[13] Broad Inst Harvard & Massachusetts Inst Technol, Cambridge, MA 02142 USA

来源：

SCIENCE | 2016年 / 354卷 / 6316期

关键词：

CHRONIC VIRAL-INFECTION; REGULATORY DNA; CHROMATIN;

D O I：

10.1126/science.aae0491

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：1165 / 1169

页数：5

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