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Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction
Open accessAbstract
T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment 1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction 2. 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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“Because Nr4a2 is highly related to Nr4a1 and has been found to promote T cell exhaustion (33-35),”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [35]
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“NFAT-induced transcription factors, including NR4A and TOX, drive T cell exhaustion/dysfunction44–47.”
From Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma (2023) · cites this paper as [45]
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Self-citationReprogramming T cell differentiation and exhaustion in CAR-T cell therapy
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“NR4A1 represses effector gene expression by inhibiting AP-1 function, and its ablation enhances antitumor immunity [91].”
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“Additionally, TCR activation following PD-1 inhibitors gave rise to partnerless NFAT lacking AP-1; NFAT interacted with NR4A and induced the transcription of exhaustion-associated genes (7, 9).”
CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome
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Clonal lineage tracing reveals mechanisms skewing CD8+ T cell fate decisions in chronic infection
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Regulators of CD8+ T cell exhaustion
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“Deleting one or more NR4A members in CD8 + T cells was demonstrated to mitigate exhaustion, preserve effector function and improve tumour control, whereas NR4A overexpression impaired effector function and accelerated exhaustion 4,5,251 .”
Self-citationRegulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression
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Fueling T-cell Antitumor Immunity: Amino Acid Metabolism Revisited
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“recruited to AP-1–binding sites, where it inhibits AP-1 activity and promotes acetylation of H3K27, which leads to tolerance-related genes and T-cell dysfunction (46).”
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“Nr4a ↑Early activation ↑Exhaustion LCMV cl-13, murine and human tumor NFAT-Nr4a/AP1 (195, 196)”
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“We did not find a prominent level of Nr4a1, a key regulator of exhaustion in CD8+ T cells (51, 52, 57), in exhausted tumor- specific CD4+ T cells; instead, CASTAT5 markedly up-regulated Nr4a1 but reduced Nr4a2 in polyfunctional CD4+ T cells (fig.”
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Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion
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“In comparison to both UT and non-TS CAR Tregs, TS-CAR Tregs had high expression of NR4A3 (NOR1) and NR4A1 (NUR77), two genes associated with exhaustion in CD8 + T cells (16, 27).”
CD8+ T cell exhaustion in the tumor microenvironment of breast cancer
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Self-citationTumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma
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NR4A1 regulates expression of immediate early genes, suppressing replication stress in cancer
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“9 A, Nur77 may simply be an indicator of the activation status of the cells, but one could also hypothesize that it directly plays a role in determining the difference in fate of Tconv cells upon conversion to pTreg cells, which is plausible given its sizeable transcriptional footprint in T cells (Fassett et al., 2012…”
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Nuclear receptor Nur77: its role in chronic inflammatory diseases
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DCision-making in tumors governs T cell anti-tumor immunity
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“The accumulation of NR4A1 -high CD4 + T cells (CD4T03) in the spleen with ageing might be explained by the combined effects of immune tolerance 29 and thymic involution.”
Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion
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Role of Epigenetic Regulation in Plasticity of Tumor Immune Microenvironment
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Self-citationAntigen-driven EGR2 expression is required for exhausted CD8+ T cell stability and maintenance
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Self-citation
Metadata
- Authors
- 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, X.-W., & Dong, C.
- Affiliations
- Army Medical University (CN)
- Institute for Systems Biology (US)
- Tsinghua University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Zhongshan Ophthalmic Center, Sun Yat-sen University (CN)
- Wuhan University (CN)
- Corresponding author
- Liu, Xindong
- Liu, Xiaolong
- Bian, Xiu-Wu
- Dong, Chen
- ORCID
- Venue
- Nature
- Published
- 2019-02-27
- Volume
- 567
- Issue
- 7749
- Pages
- 525-529
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6507425
- OpenAlex
- W2916738215
- Cited by
- 533
- References
- 30
- Citations by year
- 2026: 70 · 2025: 98 · 2024: 81 · 2023: 76 · 2022: 58 · 2021: 63 · 2020: 60 · 2019: 26
- FWCI
- 20.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL143520)
- National Cancer Institute (R03CA219760, P30CA016672)
- National Institute of Allergy and Infectious Diseases (R56AI125269, R21AI120012)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- Nur77, T cell tolerance, T cell dysfunction, AP-1, H3K27 acetylation, histone acetylation, transcriptional repression, effector T cell differentiation, regulatory T cells, cancer immunotherapy, chronic viral infection, tumour immunity, epigenetic regulation
- MeSH terms
- Acetylation, Animals, Arenaviridae Infections, Colitis, Female, Gene Expression Regulation, Histones, Immune Tolerance, Immunotherapy, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Neoplasms, T-Lymphocytes, Transcription, Genetic, Genome, Transcription Factor AP-1, Epigenesis, Genetic, Cell Line, Tumor, Mice, Nuclear Receptor Subfamily 4, Group A, Member 1
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