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

M Quigley, F Pereyra, B Nilsson, F Porichis… - Nature medicine, 2010 - nature.com
M Quigley, F Pereyra, B Nilsson, F Porichis, C Fonseca, Q Eichbaum, B Julg, JL Jesneck…
Nature medicine, 2010nature.com
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 …
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.
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