Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF

Research output: Contribution to journalArticle

Standard

Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. / Quigley, Michael; Pereyra, Florencia; Nilsson, Björn; Porichis, Filippos; Fonseca, Catia; Eichbaum, Quentin; Julg, Boris; Jesneck, Jonathan L; Brosnahan, Kathleen; Imam, Sabrina; Russell, Kate; Toth, Ildiko; Piechocka-Trocha, Alicja; Dolfi, Douglas; Angelosanto, Jill; Crawford, Alison; Shin, Haina; Kwon, Douglas S; Zupkosky, Jennifer; Francisco, Loise; Freeman, Gordon J; Wherry, E John; Kaufmann, Daniel E; Walker, Bruce D; Ebert, Benjamin; Haining, W Nicholas.

In: Nature Medicine, Vol. 16, No. 10, 10.2010, p. 1147-51.

Research output: Contribution to journalArticle

Harvard

Quigley, M, Pereyra, F, Nilsson, B, Porichis, F, Fonseca, C, Eichbaum, Q, Julg, B, Jesneck, JL, Brosnahan, K, Imam, S, Russell, K, Toth, I, Piechocka-Trocha, A, Dolfi, D, Angelosanto, J, Crawford, A, Shin, H, Kwon, DS, Zupkosky, J, Francisco, L, Freeman, GJ, Wherry, EJ, Kaufmann, DE, Walker, BD, Ebert, B & Haining, WN 2010, 'Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF', Nature Medicine, vol. 16, no. 10, pp. 1147-51. https://doi.org/10.1038/nm.2232

APA

Quigley, M., Pereyra, F., Nilsson, B., Porichis, F., Fonseca, C., Eichbaum, Q., Julg, B., Jesneck, J. L., Brosnahan, K., Imam, S., Russell, K., Toth, I., Piechocka-Trocha, A., Dolfi, D., Angelosanto, J., Crawford, A., Shin, H., Kwon, D. S., Zupkosky, J., ... Haining, W. N. (2010). Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nature Medicine, 16(10), 1147-51. https://doi.org/10.1038/nm.2232

CBE

Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, Julg B, Jesneck JL, Brosnahan K, Imam S, Russell K, Toth I, Piechocka-Trocha A, Dolfi D, Angelosanto J, Crawford A, Shin H, Kwon DS, Zupkosky J, Francisco L, Freeman GJ, Wherry EJ, Kaufmann DE, Walker BD, Ebert B, Haining WN. 2010. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nature Medicine. 16(10):1147-51. https://doi.org/10.1038/nm.2232

MLA

Vancouver

Author

Quigley, Michael ; Pereyra, Florencia ; Nilsson, Björn ; Porichis, Filippos ; Fonseca, Catia ; Eichbaum, Quentin ; Julg, Boris ; Jesneck, Jonathan L ; Brosnahan, Kathleen ; Imam, Sabrina ; Russell, Kate ; Toth, Ildiko ; Piechocka-Trocha, Alicja ; Dolfi, Douglas ; Angelosanto, Jill ; Crawford, Alison ; Shin, Haina ; Kwon, Douglas S ; Zupkosky, Jennifer ; Francisco, Loise ; Freeman, Gordon J ; Wherry, E John ; Kaufmann, Daniel E ; Walker, Bruce D ; Ebert, Benjamin ; Haining, W Nicholas. / Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. In: Nature Medicine. 2010 ; Vol. 16, No. 10. pp. 1147-51.

RIS

TY - JOUR

T1 - Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF

AU - Quigley, Michael

AU - Pereyra, Florencia

AU - Nilsson, Björn

AU - Porichis, Filippos

AU - Fonseca, Catia

AU - Eichbaum, Quentin

AU - Julg, Boris

AU - Jesneck, Jonathan L

AU - Brosnahan, Kathleen

AU - Imam, Sabrina

AU - Russell, Kate

AU - Toth, Ildiko

AU - Piechocka-Trocha, Alicja

AU - Dolfi, Douglas

AU - Angelosanto, Jill

AU - Crawford, Alison

AU - Shin, Haina

AU - Kwon, Douglas S

AU - Zupkosky, Jennifer

AU - Francisco, Loise

AU - Freeman, Gordon J

AU - Wherry, E John

AU - Kaufmann, Daniel E

AU - Walker, Bruce D

AU - Ebert, Benjamin

AU - Haining, W Nicholas

PY - 2010/10

Y1 - 2010/10

N2 - CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.

AB - CD8(+) T cells in chronic viral infections such as HIV develop functional defects including loss of interleukin-2 (IL-2) secretion and decreased proliferative potential that are collectively termed 'exhaustion'. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1), that contribute to impaired virus-specific T cell function. Although reversing PD-1 inhibition is therefore an attractive therapeutic strategy, the cellular mechanisms by which PD-1 ligation results in T cell inhibition are not fully understood. PD-1 is thought to limit T cell activation by attenuating T cell receptor (TCR) signaling. It is not known whether PD-1 also acts by upregulating genes in exhausted T cells that impair their function. Here we analyzed gene expression profiles from HIV-specific CD8(+) T cells in individuals with HIV and show that PD-1 coordinately upregulates a program of genes in exhausted CD8(+) T cells from humans and mice. This program includes upregulation of basic leucine transcription factor, ATF-like (BATF), a transcription factor in the AP-1 family. Enforced expression of BATF was sufficient to impair T cell proliferation and cytokine secretion, whereas BATF knockdown reduced PD-1 inhibition. Silencing BATF in T cells from individuals with chronic viremia rescued HIV-specific T cell function. Thus, inhibitory receptors can cause T cell exhaustion by upregulating genes--such as BATF--that inhibit T cell function. Such genes may provide new therapeutic opportunities to improve T cell immunity to HIV.

KW - Animals

KW - Antigens, CD

KW - Apoptosis Regulatory Proteins

KW - Basic-Leucine Zipper Transcription Factors

KW - CD8-Positive T-Lymphocytes

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - HIV

KW - Humans

KW - Interferon-gamma

KW - Interleukin-2

KW - Lymphocytic Choriomeningitis

KW - Mice

KW - Mice, Inbred C57BL

KW - Programmed Cell Death 1 Receptor

KW - T-Lymphocytes

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/nm.2232

DO - 10.1038/nm.2232

M3 - Article

C2 - 20890291

VL - 16

SP - 1147

EP - 1151

JO - Nature Medicine

JF - Nature Medicine

SN - 1546-170X

IS - 10

ER -