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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]
Experimental — accuracy not yet measuredIn the citing paper
“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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“In addition, elevated levels of NR4A TFs have been observed in T cells from individuals with cancer or chronic viral infections [14].”
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“NR4As genes play an essential role in T cell dysfunction and cause CAR T cells to enter an exhausted or dysfunctional state in solid tumors (43, 44).”
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“Loss of Nr4a1 also results in excessive NF-kB activation in macrophages and defective formation of T cell tolerance (31, 32).”
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“Our previous research indicates that overexpression of NR4A1 displaces chromatin-bound c-Jun, suggesting that competition with all three NR4A family members might interfere with AP-1 formation ( 23 ).”
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“Transient expression of NR4A orphan nuclear receptors has been reported in T cells after TCR ligation [43, 44], which could act cell intrinsically to inhibit effector T-cell development and induce hyporesponsiveness [45, 46].”
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“The NR4A family of transcription repressors, NR4A1 (Nur77), NR4A2 (NURR1), and NR4A3 (NOR1), was recently shown to be enriched in dysfunctional CD8 T cells and repress effector programs by being recruited to the AP-1 binding sites and inhibiting their transcriptional function (58, 59).”
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Functional subsets of tumor-specific CD8+ T cells in draining lymph nodes and tumor microenvironment
Huang, Q., Xu, L., & Ye, L. (2024) · Current Opinion in Immunology · doi:10.1016/j.coi.2024.102506 · Cited by 11
Self-citationDeng, Y., Xuan, R., Qiu, Z., Xiang, P., Guo, Y., Xu, L., Zhang, X., Mai, H., & Li, X. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.12.152 · Cited by 10
NR4A1 suppresses breast cancer growth by repressing c-Fos-mediated lipid and redox dyshomeostasis
Jiang, C., Zhu, Y., Zhang, J., Chen, H., Li, W., Xie, R., Kong, L., Chen, L., Chen, X., Huang, H., et al. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01430-3 · Cited by 11
Self-citationHdac1 as an early determinant of intermediate-exhausted CD8 + T cell fate in chronic viral infection
Hu, W., Hu, S. S., Zhu, S., Peng, W., Badovinac, V. P., Zang, C., Zhao, X., & Xue, H. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2502256122 · Cited by 12
“…and Bach2 are necessary and sufficient for promoting T EX - stem cell formation ( 10 , 11 ), Batf and Tbet are important for T EX - stem to T EX - int cell differentiation ( 8 , 12 ), while Nfat, Tox, and Nr4a activate the exhaustion program and direct the cells toward T EX - term path ( 13 – 20 ).”
Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection
Kanev, K., & Zehn, D. (2020) · Current Opinion in Virology · doi:10.1016/j.coviro.2020.10.003 · Cited by 10
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“S1E), and we see that these conditions have similar mTF activation (for mTFs; 78, 72, 57, 88, 64, 116) within the glucose conditions (Fig.”
BackgroundHerdt, O., Reich, S., Medenbach, J., Timmermann, B., Olofsson, D., Preußner, M., & Heyd, F. (2020) · RNA Biology · doi:10.1080/15476286.2020.1732701 · Cited by 10
“(D) Fold change of Nr4a1 mRNA expression in EL4 cell clones measured by RT-qPCR and normalized to HPRT (mean ± SD).”
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Wang, X., Liu, L., Zhang, L., Guo, J., Yu, L., & Li, T. (2021) · Metabolic Brain Disease · doi:10.1007/s11011-021-00866-6 · Cited by 10
“NR4A1 (also known as Nur77) is identified as the nuclear receptor 4A (NR4A) subfamily and is implicated in various biological pathways, including autophagy, apoptosis and immune response (Chen et al. 2020; Liu et al. 2019).”
BackgroundSelf-citationLamarche, C., Novakovsky, G., Qi, C. N., Weber, E. W., Mackall, C. L., & Levings, M. K. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.27.175158 · Cited by 10
“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 (Chen et al., 2019; Liu et al., 2019).”
BackgroundTumor-reactive clonotype dynamics underlying clinical response to TIL therapy in melanomaPreprint
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“ACTP n=11’900 n=123 [20-361] T30 n=14’200 n=59 [13-125] Responders”
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α-ketoglutarate suppresses immediate early gene expression in cancer cells
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Nuclear receptor 4A1 ameliorates UUO-induced renal fibrosis by inhibiting the PI3K/AKT pathway
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“NR4A1 is a key member of the nuclear receptor superfamily, which plays an important role in maintaining cell homeostasis 10 .”
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“NR4A1, a transcriptional effector of the CD8 + T -cell depletion program [47], is associated with CD8 + T -cell dysfunction [48], inhibits cytokine production in CD8 + T -cells [49], and has been found to be up-regulated in CD8 + T -cell expression.”
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“In addition, the DiNiro networks also uncovered several molecular interactions in mouse CD8+ T cells: (i) identifying the regulatory factor of HAVCR2, the NR4A1 gene (also called Nur77), which is a known critical mediator of T cell dysfunction and exhaustion in chronic inflammation and cancer (67,68).”
BackgroundRegulation and Immunotherapeutic Targeting of the Epigenome in Exhausted CD8 T Cell Responses
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Immunoregulatory Functions of Nuclear Receptors: Mechanisms and Therapeutic Implications
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Self-citationMetabolic Regulation of T Cell Exhaustion
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Tyrosinase in melanoma inhibits anti-tumor activity of PD-1 deficient T cells
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“4A. Nr4a1 is a key transcription factor that dominates expression of PD-1 [17, 18], and our finding that Nr4a1 mRNA displayed 1.79-fold increase in tyrosinase-deficient tumors was in line with the significantly elevated co-inhibitory molecule PD-1.”
InfluentialSelf-citationTargeting Lineage-Specific Functions of NR4A1 for Cancer Immunotherapy
Kleberg, J., Nataraj, A., Xiao, Y., Podder, B. R., Jin, Z., Tithi, T. I., Zheng, G., Smalley, K. S. M., Moser, E. K., Safe, S. H., et al. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26115266 · Cited by 8
“The overexpression of NR4A1 in T cells inhibits their differentiation within the TME [20].”
InfluentialEnhancing the potency of CAR-T cells against solid tumors through transcription factor engineering
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“As with TOX, NR4A TFs (NR4A1, NR4A2, NR4A3) act downstream of NFAT to induce exhaustion (33, 45–47).”
Self-citationMyers, J. A., Huang, R., Phung, S. K., Chacón, J. M., Bendzick, L. E., Weis, A., Shetty, M., DePauw, T. A., Khaw, M. J., Abrahante, J. E., et al. (2025) · Blood · doi:10.1182/blood.2024027763 · Cited by 8
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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