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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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type
Contribution to journal
publication status
published
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
in
Nature Medicine
volume
16
issue
10
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:77957781776
  • pmid:20890291
ISSN
1546-170X
DOI
10.1038/nm.2232
language
English
LU publication?
no
id
854edf4c-b63b-457c-a5bb-cdfe8dcaacec
date added to LUP
2016-10-27 13:59:24
date last changed
2024-05-04 11:27:42
@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}},
  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}},
  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}},
  doi          = {{10.1038/nm.2232}},
  volume       = {{16}},
  year         = {{2010}},
}