 Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunctionXindong Liu (),
Yun Wang,
Huiping Lu,
Jing Li,
Xiaowei Yan,
Minglu Xiao,
Jing Hao,
Andrei Alekseev,
Hiep Khong,
Tenghui Chen,
Rui Huang,
Jin Wu,
Qiwen Zhao,
Qi Wu,
Senlin Xu,
Xiaohu Wang,
Wei Jin,
Shicang Yu,
Yan Wang,
Lai Wei,
Aibo Wang,
Bo Zhong,
Ling Ni,
Xiaolong Liu,
Roza Nurieva,
Lilin Ye,
Qiang Tian,
Xiu-Wu Bian () and
Chen Dong ()
Nature, 2019, vol. 567, issue 7749, 525-529 Abstract: Abstract T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy. Date: 2019 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:567:y:2019:i:7749:d:10.1038_s41586-019-0979-8 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-019-0979-8 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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