TY - JOUR
T1 - Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction
AU - Liu, Xindong
AU - Wang, Yun
AU - Lu, Huiping
AU - Li, Jing
AU - Yan, Xiaowei
AU - Xiao, Minglu
AU - Hao, Jing
AU - Alekseev, Andrei
AU - Khong, Hiep
AU - Chen, Tenghui
AU - Huang, Rui
AU - Wu, Jin
AU - Zhao, Qiwen
AU - Wu, Qi
AU - Xu, Senlin
AU - Wang, Xiaohu
AU - Jin, Wei
AU - Yu, Shicang
AU - Wang, Yan
AU - Wei, Lai
AU - Wang, Aibo
AU - Zhong, Bo
AU - Ni, Ling
AU - Liu, Xiaolong
AU - Nurieva, Roza
AU - Ye, Lilin
AU - Tian, Qiang
AU - Bian, Xiu Wu
AU - Dong, Chen
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/3/28
Y1 - 2019/3/28
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-019-0979-8
DO - 10.1038/s41586-019-0979-8
M3 - Article
C2 - 30814730
AN - SCOPUS:85062834294
SN - 0028-0836
VL - 567
SP - 525
EP - 529
JO - Nature
JF - Nature
IS - 7749
ER -