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.
journal_name
Naturejournal_title
Natureauthors
Liu X,Wang Y,Lu H,Li J,Yan X,Xiao M,Hao J,Alekseev A,Khong H,Chen T,Huang R,Wu J,Zhao Q,Wu Q,Xu S,Wang X,Jin W,Yu S,Wang Y,Wei L,Wang A,Zhong B,Ni L,Liu X,Nurieva R,Ye L,Tian Q,Bian XW,Dong Cdoi
10.1038/s41586-019-0979-8subject
Has Abstractpub_date
2019-03-01 00:00:00pages
525-529issue
7749eissn
0028-0836issn
1476-4687pii
10.1038/s41586-019-0979-8journal_volume
567pub_type
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