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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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“Genome-wide analysis identified NR4A1 as a key inducer and general mediator of T cell dysfunction, making it a potential target for development of tumor immunotherapy [11].”
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“…RNA-binding protein, which has been reported to suppress terminal myeloid cell differentiation (Wang, Zhou, et al., 2021 ) and Treg function (Makita et al., 2020); Nr4a1 , encoding nuclear receptor subfamily 4 group A member 1 (NR4A1), a proven key mediator of T-cell dysfunction (Liu et al., 2019).”
BackgroundSelf-citationTCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma
Yakou, M. H., Ghilas, S., Tran, K., Liao, Y., Afshar‐Sterle, S., Kumari, A. N., Schmid, K., Dijkstra, C., Inguanti, C., Ostrouska, S., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.adf2163 · Cited by 30
“signaling and acts to negatively regulate T cell effector differentiation (34, 35).”
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Nr4a nuclear receptors: markers and modulators of antigen receptor signaling
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The epigenetic landscape of fate decisions in T cells
Jay, A., Pondevida, C. M., & Vahedi, G. (2025) · Nature Immunology · doi:10.1038/s41590-025-02113-x · Cited by 32
“Corroborating this observation, the ectopic expression of NR4A1, NR4A2 or NR4A3 can modify the chromatin accessibility landscape of CD8 + T cells, inducing changes characteristic of T cell exhaustion 24,25 .”
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β-glucan from Lentinus edodes inhibits breast cancer progression via the Nur77/HIF-1α axis
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“Data are representative of ≥3 independent experiments (mean SEM). sites of activator protein 1 (AP-1) instead of the AP-1 targets [26, 35, 36].”
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“In tumors, NR4A2, along with NR4A1 and NR4A3, has been shown to drive exhaustion and limit effector functions in chimeric antigen receptor T cells 27,28 , whereas in tumor-associated NK cells, NR4A2 expression is linked to reduced cytotoxic activity and a dysfunctional state 43 .”
Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging
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Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8 + T Cell Immunity against Tumor
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“The TCR-NFAT-TOX/NR4A axis holds a vital role in inducing CD8 + T cell exhaustion, facilitating the upregulation of various inhibitory receptors [19–23].”
BackgroundWen, J., Chang, X., Bai, B., Gao, Q., & Zhao, Y. (2021) · Digestive Diseases and Sciences · doi:10.1007/s10620-021-07077-0 · Cited by 27
Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer
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“28 31 In our previous work, we developed an in vitro model to generate exhausted MSLN-directed CAR T cells and showed that knocking out the transcriptional regulators inhibitor of DNA binding 3 (ID3) or SRY-box transcription factor 4 (SOX4) in CAR T cells increased their effector function upon…”
Regulatory T Cells: Pathophysiological Roles and Clinical Applications
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MEF2D-NR4A1-FAM134B2-mediated reticulophagy contributes to amino acid homeostasis
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“Considering that Nr4a1 inhibits activator protein–1 function in T cells, tumors, and endothelial cells ( 36 , 55 , 56 ) and activator protein–1 regulates the expression of several genes including Zeb2 ( 57 ), it seems likely that Nr4a1 serves as a negative regulator for ABC-driving genes in anergic…”
Sekiya, T., Kagawa, S., Masaki, K., Fukunaga, K., Yoshimura, A., & Τακακι, S. (2021) · iScience · doi:10.1016/j.isci.2021.102166 · Cited by 25
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“arthritis (3–6), T cell dysfunction (7), fibrosis (8), atherosclerosis (9) and cancer (10, 11).”
BackgroundFSTL-1 Attenuation Causes Spontaneous Smoke-Resistant Pulmonary Emphysema
Henkel, M., Partyka, J., Gregory, A. D., Forno, E., Cho, M. H., Eddens, T. J., Tout, A. R., Salamacha, N., Horne, W. T., Rao, K., et al. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201905-0973oc · Cited by 23
Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ
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Transcriptional determinants of cancer immunotherapy response and resistance
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Tang, L., Huang, Z., Mei, H., & Hu, Y. (2023) · Military Medical Research · doi:10.1186/s40779-023-00486-4 · Cited by 24
Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness
Lin, C., Levy, P. L., Alflen, A., Apriamashvili, G., Ligtenberg, M. A., Vredevoogd, D. W., Bleijerveld, O. B., Alkan, F., Malka, Y., Hoekman, L., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.02.016 · Cited by 21
Viral Hepatitides, Inflammation and Tumour Microenvironment
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Reticker-Flynn, N. E., & Engleman, E. G. (2020) · eLife · doi:10.7554/elife.53839 · Cited by 23
“NR4A1 transcription factor in instilling the TEx state by inhibiting binding of the AP-1 transcription factor to binding sites of effector-related genes (Liu et al., 2019).”
BackgroundNR4A1 agonist cytosporone B attenuates neuroinflammation in a mouse model of multiple sclerosis
Wang, L., Yu, H.-Z., Zhu, B.-Q., Zhu, L. D., & Li, S. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.339492 · Cited by 22
“Additionally, NR4A family members regulate gene expression that is related to cell differentiation, proliferation, and programmed death (Winoto and Littman, 2002; Liu et al., 2019; He et al., 2020).”
BackgroundBis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion
Mohankumar, K., Wright, G. A., Kumaravel, S., Shrestha, R., Zhang, L., Abdelrahim, M., Chapkin, R. S., & Safe, S. H. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03530-3 · Cited by 24
“Since NR4A1 is a key mediator of T-cell dysfunction [27] and has been associated with CD8 + T-cell exhaustion, we further investigated the potential role of NR4A1 antagonists DIM-3,5-Cl 2 and DIM-3-Br-5-OCF 3 in decreasing some of the markers of CD8 + and CD4 + T-cell exhaustion associated with the…”
BackgroundSchmassmann, P., Roux, J., Dettling, S., Hogan, S. A., Shekarian, T., Martins, T. A., Ritz, M., Herter, S., Bacac, M., & Hütter, G. (2023) · eLife · doi:10.7554/elife.92678 · Cited by 32
Lalle, G., Lautraite, R., Bouherrou, K., Plaschka, M., Pignata, A., Voisin, A., Twardowski, J., Perrin-Niquet, M., Stéphan, P., Durget, S., et al. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231348 · Cited by 21
“Interestingly, by using public ChIP-Seq databases in T cells (Liu et al., 2019), we found that BATF and c-Jun were bound to nearly all 684 genes indirectly regulated by RelA (Fig.”
Functional heterogeneity and adaptation of naive T cells in response to tonic TCR signals
Eggert, J., & Au‐Yeung, B. B. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.09.007 · Cited by 20
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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