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

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 -