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

Abstract 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.
PMID
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Authors

Mayor MeshTerms

Gene Expression Profiling

Keywords
Journal Title nature medicine
Publication Year Start
%A Quigley, Michael; Pereyra, Florencia; Nilsson, Bj?rn; 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
%T Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
%J Nature medicine, vol. 16, no. 10, pp. 1147-1151
%D 10/2010
%V 16
%N 10
%M eng
%B 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.
%K Animals, Antigens, CD, Apoptosis Regulatory Proteins, Basic-Leucine Zipper Transcription Factors, CD8-Positive T-Lymphocytes, Gene Expression Profiling, Gene Expression Regulation, HIV, Humans, Interferon-gamma, Interleukin-2, Lymphocytic Choriomeningitis, Mice, Mice, Inbred C57BL, Programmed Cell Death 1 Receptor, T-Lymphocytes
%P 1147
%L 1151
%Y 10.1038/nm.2232
%W PHY
%G AUTHOR
%R 2010Natur..16.1147Q

@Article{Quigley2010,
author="Quigley, Michael
and Pereyra, Florencia
and Nilsson, Bj{\"o}rn
and Porichis, Filippos
and Fonseca, Catia
and Eichbaum, Quentin
and Julg, Boris
and Jesneck, Jonathan L.
and Brosnahan, Kathleen
and Imam, Sabrina
and Russell, Kate
and Toth, Ildiko
and Piechocka-Trocha, Alicja
and Dolfi, Douglas
and Angelosanto, Jill
and Crawford, Alison
and Shin, Haina
and Kwon, Douglas S.
and Zupkosky, Jennifer
and Francisco, Loise
and Freeman, Gordon J.
and Wherry, E. John
and Kaufmann, Daniel E.
and Walker, Bruce D.
and Ebert, Benjamin
and Haining, W. Nicholas",
title="Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.",
journal="Nature medicine",
year="2010",
month="Oct",
day="03",
volume="16",
number="10",
pages="1147--1151",
keywords="Animals",
keywords="Antigens, CD",
keywords="Apoptosis Regulatory Proteins",
keywords="Basic-Leucine Zipper Transcription Factors",
keywords="CD8-Positive T-Lymphocytes",
keywords="Gene Expression Profiling",
keywords="Gene Expression Regulation",
keywords="HIV",
keywords="Humans",
keywords="Interferon-gamma",
keywords="Interleukin-2",
keywords="Lymphocytic Choriomeningitis",
keywords="Mice",
keywords="Mice, Inbred C57BL",
keywords="Programmed Cell Death 1 Receptor",
keywords="T-Lymphocytes",
abstract="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.",
issn="1546-170X",
doi="10.1038/nm.2232",
url="http://www.ncbi.nlm.nih.gov/pubmed/20890291",
language="eng"
}

%0 Journal Article
%T Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
%A Quigley, Michael
%A Pereyra, Florencia
%A Nilsson, Bj?rn
%A Porichis, Filippos
%A Fonseca, Catia
%A Eichbaum, Quentin
%A Julg, Boris
%A Jesneck, Jonathan L.
%A Brosnahan, Kathleen
%A Imam, Sabrina
%A Russell, Kate
%A Toth, Ildiko
%A Piechocka-Trocha, Alicja
%A Dolfi, Douglas
%A Angelosanto, Jill
%A Crawford, Alison
%A Shin, Haina
%A Kwon, Douglas S.
%A Zupkosky, Jennifer
%A Francisco, Loise
%A Freeman, Gordon J.
%A Wherry, E. John
%A Kaufmann, Daniel E.
%A Walker, Bruce D.
%A Ebert, Benjamin
%A Haining, W. Nicholas
%J Nature medicine
%D 2010
%8 Oct 03
%V 16
%N 10
%@ 1546-170X
%G eng
%F Quigley2010
%X 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.
%K Animals
%K Antigens, CD
%K Apoptosis Regulatory Proteins
%K Basic-Leucine Zipper Transcription Factors
%K CD8-Positive T-Lymphocytes
%K Gene Expression Profiling
%K Gene Expression Regulation
%K HIV
%K Humans
%K Interferon-gamma
%K Interleukin-2
%K Lymphocytic Choriomeningitis
%K Mice
%K Mice, Inbred C57BL
%K Programmed Cell Death 1 Receptor
%K T-Lymphocytes
%U http://dx.doi.org/10.1038/nm.2232
%U http://www.ncbi.nlm.nih.gov/pubmed/20890291
%P 1147-1151

PT Journal
AU 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
TI Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
SO Nature medicine
JI Nat. Med.
PD Oct
PY 2010
BP 1147
EP 1151
VL 16
IS 10
DI 10.1038/nm.2232
LA eng
DE Animals; Antigens, CD; Apoptosis Regulatory Proteins; Basic-Leucine Zipper Transcription Factors; CD8-Positive T-Lymphocytes; Gene Expression Profiling; Gene Expression Regulation; HIV; Humans; Interferon-gamma; Interleukin-2; Lymphocytic Choriomeningitis; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor; T-Lymphocytes
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.
ER

PMID- 20890291
OWN - NLM
STAT- MEDLINE
DA  - 20101008
DCOM- 20101104
LR  - 20160114
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 16
IP  - 10
DP  - 2010 Oct
TI  - Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T 
      cell function by upregulating BATF.
PG  - 1147-51
LID - 10.1038/nm.2232 [doi]
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.
FAU - Quigley, Michael
AU  - Quigley M
AD  - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical
      School, Boston, Massachusetts, USA.
FAU - Pereyra, Florencia
AU  - Pereyra F
FAU - Nilsson, Bjorn
AU  - Nilsson B
FAU - Porichis, Filippos
AU  - Porichis F
FAU - Fonseca, Catia
AU  - Fonseca C
FAU - Eichbaum, Quentin
AU  - Eichbaum Q
FAU - Julg, Boris
AU  - Julg B
FAU - Jesneck, Jonathan L
AU  - Jesneck JL
FAU - Brosnahan, Kathleen
AU  - Brosnahan K
FAU - Imam, Sabrina
AU  - Imam S
FAU - Russell, Kate
AU  - Russell K
FAU - Toth, Ildiko
AU  - Toth I
FAU - Piechocka-Trocha, Alicja
AU  - Piechocka-Trocha A
FAU - Dolfi, Douglas
AU  - Dolfi D
FAU - Angelosanto, Jill
AU  - Angelosanto J
FAU - Crawford, Alison
AU  - Crawford A
FAU - Shin, Haina
AU  - Shin H
FAU - Kwon, Douglas S
AU  - Kwon DS
FAU - Zupkosky, Jennifer
AU  - Zupkosky J
FAU - Francisco, Loise
AU  - Francisco L
FAU - Freeman, Gordon J
AU  - Freeman GJ
FAU - Wherry, E John
AU  - Wherry EJ
FAU - Kaufmann, Daniel E
AU  - Kaufmann DE
FAU - Walker, Bruce D
AU  - Walker BD
FAU - Ebert, Benjamin
AU  - Ebert B
FAU - Haining, W Nicholas
AU  - Haining WN
LA  - eng
SI  - GEO/GSE24082
GR  - AI082630/AI/NIAID NIH HHS/United States
GR  - AI56299/AI/NIAID NIH HHS/United States
GR  - HHSN26620050030C/PHS HHS/United States
GR  - HL092565/HL/NHLBI NIH HHS/United States
GR  - P01 AI080192/AI/NIAID NIH HHS/United States
GR  - R01 AI030914/AI/NIAID NIH HHS/United States
GR  - R01 HL092565/HL/NHLBI NIH HHS/United States
GR  - R21 CA129670/CA/NCI NIH HHS/United States
GR  - R21 CA129670-02/CA/NCI NIH HHS/United States
GR  - U19 AI057266/AI/NIAID NIH HHS/United States
GR  - U19 AI057266-068186/AI/NIAID NIH HHS/United States
GR  - U19 AI082630/AI/NIAID NIH HHS/United States
GR  - U19 AI082630-018631/AI/NIAID NIH HHS/United States
GR  - U19 AI090023/AI/NIAID NIH HHS/United States
GR  - U19 AI090023-015527/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101003
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Antigens, CD)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BATF protein, human)
RN  - 0 (Basic-Leucine Zipper Transcription Factors)
RN  - 0 (Batf protein, mouse)
RN  - 0 (Interleukin-2)
RN  - 0 (PDCD1 protein, human)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
CIN - Nat Rev Immunol. 2010 Nov;10(11):747. PMID: 21080609
MH  - Animals
MH  - Antigens, CD/*physiology
MH  - Apoptosis Regulatory Proteins/*physiology
MH  - Basic-Leucine Zipper Transcription Factors/*genetics
MH  - CD8-Positive T-Lymphocytes/*metabolism
MH  - *Gene Expression Profiling
MH  - Gene Expression Regulation
MH  - HIV/*immunology
MH  - Humans
MH  - Interferon-gamma/biosynthesis
MH  - Interleukin-2/biosynthesis
MH  - Lymphocytic Choriomeningitis/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Programmed Cell Death 1 Receptor
MH  - T-Lymphocytes/*physiology
PMC - PMC3326577
MID - NIHMS234681
OID - NLM: NIHMS234681
OID - NLM: PMC3326577
EDAT- 2010/10/05 06:00
MHDA- 2010/11/05 06:00
CRDT- 2010/10/05 06:00
PHST- 2010/07/13 [received]
PHST- 2010/09/07 [accepted]
PHST- 2010/10/03 [aheadofprint]
AID - nm.2232 [pii]
AID - 10.1038/nm.2232 [doi]
PST - ppublish
SO  - Nat Med. 2010 Oct;16(10):1147-51. doi: 10.1038/nm.2232. Epub 2010 Oct 3.
TY  - JOUR
AU  - Quigley, Michael
AU  - Pereyra, Florencia
AU  - Nilsson, Bj?rn
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/Oct/03
TI  - Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.
T2  - Nat. Med.
JO  - Nature medicine
SP  - 1147
EP  - 1151
VL  - 16
IS  - 10
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
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.
SN  - 1546-170X
UR  - http://dx.doi.org/10.1038/nm.2232
UR  - http://www.ncbi.nlm.nih.gov/pubmed/20890291
ID  - Quigley2010
ER  - 
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<b:Title>Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF.</b:Title>
 <b:ShortTitle>Nat. Med.</b:ShortTitle>
<b:Comments>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 &apos;exhaustion&apos;. 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.</b:Comments>
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