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

Research output: Contribution to journalArticle


title = "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.",
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",
author = "Michael Quigley and Florencia Pereyra and Bj{\"o}rn Nilsson and Filippos Porichis and Catia Fonseca and Quentin Eichbaum and Boris Julg and Jesneck, {Jonathan L} and Kathleen Brosnahan and Sabrina Imam and Kate Russell and Ildiko Toth and Alicja Piechocka-Trocha and Douglas Dolfi and Jill Angelosanto and Alison Crawford and Haina Shin and Kwon, {Douglas S} and Jennifer Zupkosky and Loise Francisco and Freeman, {Gordon J} and Wherry, {E John} and Kaufmann, {Daniel E} and Walker, {Bruce D} and Benjamin Ebert and Haining, {W Nicholas}",
year = "2010",
month = oct,
doi = "10.1038/nm.2232",
language = "English",
volume = "16",
pages = "1147--51",
journal = "Nature Medicine",
issn = "1546-170X",
publisher = "Nature Publishing Group",
number = "10",