The epigenetic landscape of T cell exhaustion

Debattama R. Sen; James Kaminski; R. Anthony Barnitz; Makoto Kurachi; Ulrike Gerdemann; Kathleen B. Yates; Hsiao-Wei Tsao; Jernej Godec; Martin W. LaFleur; Flavian D. Brown; Pierre Tonnerre; Raymond T. Chung; Damien C. Tully; Todd M. Allen; Nicole Frahm; Georg M. Lauer; E. John Wherry; Nir Yosef; W. Nicholas Haining

doi:https://doi.org/10.1126/science.aae0491

The epigenetic landscape of T cell exhaustion

Debattama R. Sen, James Kaminski, R. Anthony Barnitz, Makoto Kurachi, Ulrike Gerdemann, Kathleen B. Yates, Hsiao-Wei Tsao, Jernej Godec, Martin W. LaFleur, Flavian D. Brown, Pierre Tonnerre, Raymond T. Chung, Damien C. Tully, Todd M. Allen, Nicole Frahm, Georg M. Lauer, E. John Wherry, Nir Yosef, W. Nicholas Haining

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1165-1169
Number of pages	5
Journal	Science
Volume	354
Issue number	6316
Early online date	27 Oct 2016
DOIs	https://doi.org/10.1126/science.aae0491
State	Published - 2 Dec 2016
Externally published	Yes

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Sen, D. R., Kaminski, J., Barnitz, R. A., Kurachi, M., Gerdemann, U., Yates, K. B., Tsao, H-W., Godec, J., LaFleur, M. W., Brown, F. D., Tonnerre, P., Chung, R. T., Tully, D. C., Allen, T. M., Frahm, N., Lauer, G. M., Wherry, E. J., Yosef, N., & Haining, W. N. (2016). The epigenetic landscape of T cell exhaustion. Science, 354(6316), 1165-1169. Advance online publication. https://doi.org/10.1126/science.aae0491

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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.",

author = "Sen, {Debattama R.} and James Kaminski and Barnitz, {R. Anthony} and Makoto Kurachi and Ulrike Gerdemann and Yates, {Kathleen B.} and Hsiao-Wei Tsao and Jernej Godec and LaFleur, {Martin W.} and Brown, {Flavian D.} and Pierre Tonnerre and Chung, {Raymond T.} and Tully, {Damien C.} and Allen, {Todd M.} and Nicole Frahm and Lauer, {Georg M.} and Wherry, {E. John} and Nir Yosef and Haining, {W. Nicholas}",

year = "2016",

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doi = "https://doi.org/10.1126/science.aae0491",

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AU - Sen, Debattama R.

AU - Kaminski, James

AU - Barnitz, R. Anthony

AU - Kurachi, Makoto

AU - Gerdemann, Ulrike

AU - Yates, Kathleen B.

AU - Tsao, Hsiao-Wei

AU - Godec, Jernej

AU - LaFleur, Martin W.

AU - Brown, Flavian D.

AU - Tonnerre, Pierre

AU - Chung, Raymond T.

AU - Tully, Damien C.

AU - Allen, Todd M.

AU - Frahm, Nicole

AU - Lauer, Georg M.

AU - Wherry, E. John

AU - Yosef, Nir

AU - Haining, W. Nicholas

PY - 2016/12/2

Y1 - 2016/12/2

N2 - 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.

AB - 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.

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DO - https://doi.org/10.1126/science.aae0491

M3 - مقالة

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SN - 0036-8075

VL - 354

SP - 1165

EP - 1169

JO - Science

JF - Science

IS - 6316

ER -

The epigenetic landscape of T cell exhaustion

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