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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We thank the C.D., X.L. and X.-W.B. laboratory members for their assistance and O. M. Conneely for the Nr4a1−/− mouse strain. The study was supported by the National Key Research and Development Program of China (2016YFA0101200 to X.L. and X.-W.B.); Beijing Municipal Science and Technology (Z171100000417005 to C.D.); the Ministry of Science and Technology of China (2016YFC0906200 to C.D.); the National Natural Science Foundation of China (31630022 and 91642201 to C.D., and 31770973 to X.L.); the Natural Science Foundation Project of Chongqing (CSTC2014JCYJYS10001 to X.L.); an Institute Project grant (SWH2015QN07 and SWH2016HWHZ-01 to X.L.); an Odyssey Fellowship (to X.L.) from MD Anderson Cancer Center; and NIH grants (R01HL143520, R56AI125269, R21AI120012 and R03CA219760 to R.N.).
Nature thanks Golnaz Vahedi and the other anonymous reviewer(s) for their contribution to the peer review of this work.