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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 LU ; Porichis, Filippos; Fonseca, Catia; Eichbaum, Quentin; Julg, Boris; Jesneck, Jonathan L; Brosnahan, Kathleen and Imam, Sabrina, et al. (2010) In Nature Medicine 16(10). p.51-1147
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... (More)

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.

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keywords
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, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
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Nature Medicine
volume
16
issue
10
pages
5 pages
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Nature Publishing Group
external identifiers
  • scopus:77957781776
ISSN
1546-170X
DOI
10.1038/nm.2232
language
English
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no
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854edf4c-b63b-457c-a5bb-cdfe8dcaacec
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2016-10-27 13:59:24
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2018-12-02 04:44:01
@article{854edf4c-b63b-457c-a5bb-cdfe8dcaacec,
  abstract     = {<p>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.</p>},
  author       = {Quigley, Michael and Pereyra, Florencia and Nilsson, Björn 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},
  issn         = {1546-170X},
  keyword      = {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,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {10},
  pages        = {51--1147},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF},
  url          = {http://dx.doi.org/10.1038/nm.2232},
  volume       = {16},
  year         = {2010},
}