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• W1997241837 abstract "The inhibitory receptor programmed death-1 (PD-1) is upregulated on exhausted CD8+ T cells in HIV-infected individuals. Quigley et al. analyzed the transcriptional profile induced by PD-1 ligation and report that a transcription factor, BATF, is upregulated by PD-1 signaling and has a key role in PD-1–mediated inhibition of T cell function. 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'1. Exhausted T cells express increased amounts of multiple inhibitory receptors, such as programmed death-1 (PD-1)2,3, 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) signaling4,5. 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." @default.
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• W1997241837 date "2010-10-01" @default.
• W1997241837 modified "2023-10-16" @default.
• W1997241837 title "Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF" @default.
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• W1997241837 doi "https://doi.org/10.1038/nm.2232" @default.
• W1997241837 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3326577" @default.
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• W1997241837 hasPublicationYear "2010" @default.
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