The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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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Cites
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
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Super-enhancers in the control of cell identity and disease
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Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation
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Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., et al. (2016) · Science · doi:10.1126/science.aaf2807 · Cited by 1,348
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Self-citationThe epigenetic landscape of T cell exhaustion
Sen, D. R., Kaminski, J., Barnitz, R. A., Kurachi, M., Gerdemann, U., Yates, K. B., Tsao, H.-W., Godec, J., LaFleur, M. W., Brown, F. D., et al. (2016) · Science · doi:10.1126/science.aae0491 · Cited by 986
The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells
Martinez, G. J., Pereira, R. M., Äijö, T., Kim, E. Y., Marangoni, F., Pipkin, M. E., Togher, S., Heissmeyer, V., Zhang, Y. C., Crotty, S., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.006 · Cited by 857
Tolerance and exhaustion: defining mechanisms of T cell dysfunction
Schietinger, A., & Greenberg, P. D. (2013) · Trends in Immunology · doi:10.1016/j.it.2013.10.001 · Cited by 704
Cited by
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Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603
CD8+ T cell differentiation and dysfunction in cancer
Philip, M., & Schietinger, A. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00574-3 · Cited by 1,052
Clinical implications of T cell exhaustion for cancer immunotherapy
Chow, A., Perica, K., Klebanoff, C. A., & Wolchok, J. D. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00689-z · Cited by 1,044
Sun, L., Su, Y., Jiao, A., Wang, X., & Zhang, B. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01471-y · Cited by 1,153
Self-citationc-Jun overexpression in CAR T cells induces exhaustion resistance
Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., et al. (2019) · Nature · doi:10.1038/s41586-019-1805-z · Cited by 891
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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