Cited by 535T-cell and B-cell ImmunologyNuclear Receptors and SignalingCancer Immunotherapy and Biomarkers

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Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

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Liu, Xindong, Wang, Yun, Lu, Huiping, Li, Jing, Yan, Xiaowei, Xiao, Minglu, Hao, Jing, Alekseev, Andrei, Khong, Hiep, Chen, Tenghui, Huang, Rui, Wu, Jin, Zhao, Qiwen, Wu, Qi, Xu, Senlin, Wang, Xiaohu, Jin, Wei, Yu, Shicang, Wang, Yan, Wei, Lai, Wang, Aibo, Zhong, Bo, Ni, Ling, Liu, Xiaolong, Nurieva, Roza, Ye, Lilin, Tian, Qiang, Bian, Xiu-Wu, Dong, Chen·2019·Nature

DOI 10.1038/s41586-019-0979-8PMC PMC6507425

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Abstract

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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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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Wei, G., Wei, L., Zhu, J., Zang, C., Hu-Li, J., Yao, Z., Cui, K., Kanno, Y., Roh, T.-Y., Watford, W. T., et al. (2009) · Immunity · doi:10.1016/j.immuni.2008.12.009 · Cited by 1,152
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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

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Lam, V. C., Barragan, J., Cheung, C., Lü, J., Chian, D., Martinez, R., Sims, C., Sundar, P. D., Hiraragi, H., Potluri, S., et al. (2022) · Regular and Young Investigator Award Abstracts · doi:10.1136/jitc-2022-sitc2022.0243 · Cited by 1
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Self-citation
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Xiao, B., Zhang, Y., Liu, S., Ding, J., Yu, Z., Wang, T., & Song, B. (2020) · Transplantation Proceedings · doi:10.1016/j.transproceed.2020.08.023 · Cited by 1
[Fuxinfang improves hypoxia-induced injury of human aortic endothelial cells by regulating c-Fos-NR4A1-p38 pathway].
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“[41] Liu, X, Wang, Y, Lu, H, Li, J, Yan, X, Xiao, M, .”
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Mogus, J. P., Marin, M., Arowolo, O. K., Salemme, V., & Suvorov, A. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.04.574224 · Cited by 1
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Porte, A. L., Pathak, R., Eliscovich, C., Martins, L. J., Nell, R., Spivak, A. M., Suzuki, M., Planelles, V., Singer, R. H., & Kalpana, G. V. (2024) · Research Square · doi:10.21203/rs.3.rs-4166090/v1 · Cited by 1
The transcription factor BATF pioneers the differentiation program of cytolytic effector CD8 + T cells through the direct interaction with IRF4Preprint
Fujisawa, S., Tanabe, Y., Hojo, A., Shiga, R., Kurachi, J., Koura, M., Tamai, T., Miyanari, Y., Wherry, E. J., & Kurachi, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.21.605975 · Cited by 1
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Fumagalli, M., An, D., Simula, L., Combe, C., Aziez, L., Simoni, Y., Alves‐Guerra, M., Valentini, A., Marchais, M., Vermare, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.28.645780 · Cited by 1
SIRPγ modulates effector differentiation of human CD8 T Cells under suboptimal TCR stimulation: implications for immune homeostasis and autoimmunityPreprint
Morse, M., Rodriguez, X., DeLaRosa, E., Rodriguez, S. G., Shanil, J., & Sinha, S. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.09.663913 · Cited by 1
Integrated Single Cell Analysis Identifies CD39+ Tumor-Associated NK Cells with Cytotoxic Potential in Lung CancerPreprint
Serger, C., Rebuffet, L., Sandholzer, M. T., Fusi, I., Oelgarth, N., Tundo, S., Luu, T. T., Hojski, A., Lardinois, D., Trefny, M. P., et al. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5356127 · Cited by 1
Systematic Comparison of 10X Genomics and Parse Single Cell RNA Technologies across PBMC and CD8 + TEMRA CellsPreprint
Espinoza, A., Silva, B. J. D. A., & Pellegrini, M. A. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.02.748788 · Cited by 1
Differential impact of TNFRSF co-stimulation on CD8 + T cell cytokine production by feedback control of surface receptor expressionPreprint
Nguyen, J., Pettmann, J., Kruger, P., & Dushek, O. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.02.450833
“Alternatively, ‘armored’ CAR T cells engineered to inducibly produce pro-inflammatory cytokines in order to adjust the tumour microenvironment in their favour have been proposed (53).”
Background
[The direct isotopic cystography in the study of the vesico-ureteral reflux (author's transl)].
Cortázar, J. C. F., González, J. S., Terol, M. C. C., Monfort, J. A., & Marti, I. Z. (1978) · PubMed
Single-Cell RNA Sequencing Reveals Tumor Microenvironment Remodeling after Neoadjuvant Immunotherapy in Non-small Cell Lung CancerPreprint
Hu, J., zhang, L., Xia, H., Yan, Y., Zhu, X., Sun, F., Sun, L., Li, S., Li, D., Wang, J., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-934132/v1
732 A novel nuclear receptor 4A1 (NR4A1) antagonists attenuates T-cell exhaustion in colorectal cancer
Mohankumar, K., Wright, G. A., Kumaravel, S., Shrestha, R., Abdelrahim, M., Chapkin, R. S., & Safe, S. H. (2021) · Regular and Young Investigator Award Abstracts · doi:10.1136/jitc-2021-sitc2021.732
“fied NR4A1 as a key mediator of T-cell dysfunction and NR4A1 also plays an important role in regulating genes which are involved in tumor-induced T-cell exhaustion.(9) Bis-indole”
Background
CD69-OxLDL Ligand Engagement Induces Programmed Cell Death 1 (PD-1) Expression in T LymphocytesPreprint
Jiménez-Fernández, M., Rodriguez-Sinovas, C., Cañes, L., Ballester‐Servera, C., Vara, A., Requena, S., de la Fuente, H., Martínez‐González, J., & Sánchez‐Madrid, F. (2022) · Research Square · doi:10.21203/rs.3.rs-1373760/v1
Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating T cellsPreprint
Riegel, D., Romero-Fernández, E., Simon, M., Adenugba, A. R., Singer, K., Mayr, R., Weber, F., Imbusch, C. D., Kreutz, M. P., Brors, B., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.03.16.484513
Faculty Opinions recommendation of c-Jun overexpression in CAR T cells induces exhaustion resistance.
Pawelec, G. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.737026147.793569308
Profile of Dr. Chen Dong
(2022) · Science China Life Sciences · doi:10.1007/s11427-022-2101-x
“Dr. Dong’s group has ongoing research to understand the molecular mechanisms of CD8+ T cell dysfunction in cancer, and has shown critical roles for Eomes (Li et al., 2018a) and Nr4a1 (Liu et al., 2019) transcription factors.”
Background
Introduction: Redefining T-cell Exhaustion Special Issue
Kagoya, Y., & Togashi, Y. (2022) · International Immunology · doi:10.1093/intimm/dxac043
NR4A3 deficiency in CD8 + T cells improves adoptive T cell therapy of cancerPreprint
Odagiu, L., Mezrag, S., Sousa, D. M. D., Boulet, S., & Labrecque, N. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.21.537841
Alternative paths to immune activation: the role of costimulatory risk genes for polygenic inflammatory disease in T helper cellsPreprint
Voda, A.-I., Correa, K., Hamp, J., Moscrop, C., Dustin, M. L., & Jostins-Dean, L. (2023) · doi:10.7554/elife.86891.1
Alternative paths to immune activation: the role of costimulatory risk genes for polygenic inflammatory disease in T helper cellsPreprint
Voda, A.-I., Correa, K., Hamp, J., Moscrop, C., Dustin, M. L., & Jostins-Dean, L. (2023) · doi:10.7554/elife.86891
Rapid identification of key genes for the rod-shaped morphology in bacteria using multi-species genomesPreprint
Liu, Q., Liu, H., Xu, C., Shi, J., Xie, Y., Hu, S., & Han, G. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.14.548972
“Unraveling their functions is crucial for elucidating the basic principles of life, investigating biological development and evolution, and uncovering the underlying mechanisms of disease occurrence[2, 4].”
Background
Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer ImmunotherapyPreprint
Wang, L. A., Xiao, Y., Luo, Y., Master, R. P., Mo, J., Kim, M., Liu, Y., Patel, U. M., Li, X., Shaffer, D. R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.09.552650
Nur77 Inhibit β-catenin Expression to Mediate Hepatoblastoma Progression and Therapeutic Effect of CisplatinPreprint
Zhou, J., Liu, X., Yin, H., Zhou, Y. F., Xu, Z., Zhou, K., Li, T., Fang, Y., & Shen, Q. (2023) · Research Square · doi:10.21203/rs.3.rs-3350840/v1
Self-citation
Additional file 3 of Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing
Hu, J., Zhang, L., Xia, H., Yan, Y., Zhu, X., Sun, F., Sun, L., Li, S., Li, D., Wang, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617403
Additional file 1 of Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing
Hu, J., Zhang, L., Xia, H., Yan, Y., Zhu, X., Sun, F., Sun, L., Li, S., Li, D., Wang, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617394
Additional file 4 of Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing
Hu, J., Zhang, L., Xia, H., Yan, Y., Zhu, X., Sun, F., Sun, L., Li, S., Li, D., Wang, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617406
Reviewer #2 (Public Review): Single-cell characterization of human GBM reveals regional differences in tumor-infiltrating leukocyte activation
Schmassmann, P., Roux, J., Dettling, S., et al. (2023) · eLife · doi:10.7554/elife.92678.1.sa0
Transcriptional control of central T cell tolerance by NR4A family nuclear receptorsPreprint
Nielsen, H. V., Mueller, J. L., Hiwa, R., Yang, L., Proekt, I., Rackaityte, E., Aylard, D. A., Scharer, C. D., Anderson, M. S., Au‐Yeung, B. B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.19.594881
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Semitekolou, M., Paschalidis, N., Tartaro, D. L., Tsitsopoulou, A., Stamou, P., Mavroudis, A., Markaki, E., Varveri, A., Morianos, I., Lavigne, M. D., et al. (2024) · medRxiv · doi:10.1101/2024.08.27.24312529
“PD-L1 + CD8 + T cells expressed higher levels of genes associated with T cell immune suppression or exhaustion, including NR4A1, IGFBP2 and LAYN 29-31 , ( Fig.”
BackgroundResultInfluential
A lymphoid tissue chemokine checkpoint prevents loss of CD8 + T cell functionalityPreprint
Altenburger, L. M., Carvoeiro, D. C., Dehio, P., Zhou, J., Laura, C., Katoch, M., Krueger, C., de Albuquerque, J. B., Pfenninger, P., Magdaleno, J. M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.19.613830
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Zhang, Y., Cheng, J., Jin, P., Lv, L., Yu, H., Yang, C., & Zhang, S. (2024) · Technology and Health Care · doi:10.1177/09287329241290937
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Pouxvielh, K., Marotel, M., Rousseaux, N., Picq, L., Benezech, S., Nombel, A., Kern, N., Marçais, A., & Walzer, T. (2025) · Springer eBooks · doi:10.1007/978-3-662-68816-8_30-1
Multidisciplinary integration and fusion based on critical care medicine and immunology: History, current status, and prospects.
Shi, J., & Lü, B. (2024) · PubMed Central · doi:10.11817/j.issn.1672-7347.2024.240220
“Additionally, professor DONG Chen and QI Hai [50-53] , 2 Chinese scholars, have achieved internationally leading research outcomes in adaptive immunity, particularly in studies of T and B lymphocytes, closely related to late-stage immune suppression in critical illness.”
Multi-omics for disease subtyping and classification
Sherif, S., Hendi, N. N., & Alanany, R. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-13595-8.00005-2
Dissecting the causal role of immunophenotypes in brain meningioma risk: A Mendelian randomization study
Zhu, X., Wang, Y., Liu, Z., Zhang, X., Zhang, S., Pang, B., & Zhu, S. (2025) · Medicine · doi:10.1097/md.0000000000042678
Self-citation
LncRNA Dleu2 Serve as a Novel Biomarker for Ablation Recurrence and Promote Atrial Remodelling by Targeting Nr4a1 in Atrial Fibrillation
Wei, F., Ma, Y., Xiang, H., Zhang, X., & Fan, J. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70618
“Nr4a1, a member of the nuclear receptor superfamily related to steroid, thyroid and retinoid receptors, has been implicated in diverse biological processes, including T cell regulation, inflammatory responses, apoptosis and fibrotic pathways [48–50].”
Phenotypic, Functional and Transcriptional Heterogeneity in T Cell Exhaustion
Zander, R., & Cui, W. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00278-7
CD39 defines a cytotoxic tumor-associated NK cell state responsive to NKG2A blockade in lung cancerPreprint
Serger, C., Rebuffet, L., Sandholzer, M., Rackwitz, W., Fusi, I., Herzig, P., Brüggemann, A., Pawlow, C., Chichelnitskiy, E., Hajnal, D., et al. (2026) · bioRxiv · doi:10.1101/2025.08.26.672316
“For instance, NR4A1 drives T cell exhaustion via suppression of AP1-mediated activation (74) , while IRF4 is implicated in both, NK and T cell activation and effector function (75, 76, 104) .”
CD7 drives CD8 T cell exhaustion during chronic viral infection
Reisch, K. M., Scherer, A., Bartell, R., Santana, F., Shao, P., Butler, N. S., & Zander, R. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkaf283.1625
Additional file 1 of Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response
Wang, A. Z., Bowman-Kirigin, J. A., Desai, R., Kang, L.-I., Patel, P. R., Patel, B., Khan, S. M., Bender, D. E., Marlin, M. C., Liu, J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19736402
Self-citation
Additional file 2 of Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing
Hu, J., zhang, L., Xia, H., Yan, Y., Zhu, X., Sun, F., Sun, L., Li, S., Li, D., Wang, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22617400
Additional file 2 of Structure-primed embedding on the transcription factor manifold enables transparent model architectures for gene regulatory network and latent activity inference
Tjärnberg, A., Beheler-Amass, M., Jackson, C. A., Christiaen, L., Gresham, D., & Bonneau, R. (2024) · Figshare · doi:10.6084/m9.figshare.26669286
Additional file 1 of Structure-primed embedding on the transcription factor manifold enables transparent model architectures for gene regulatory network and latent activity inference
Tjärnberg, A., Beheler-Amass, M., Jackson, C. A., Christiaen, L., Gresham, D., & Bonneau, R. (2024) · Figshare · doi:10.6084/m9.figshare.26669283
Intermittent Tacrolimus Treatment Delays CD8+ Tumor‐Infiltrating Lymphocyte Exhaustion and Enhances PD1 Blockade Therapy in Melanoma‐Bearing Mice
Chen, D., Feng, S., Chen, Z., Weng, Z., Zhang, S., Lin, J., & Wang, Z. (2026) · Journal of Immunology Research · doi:10.1155/jimr/8444562
Host gene expression changes induced by an HIV-1 mutant associated with delayed AIDS progression reveal potential mechanismsPreprint
Sithole, S. T., Ramsey, J. S., Call, M. C., Poole, B. D., Pickett, B. E., & Berges, B. K. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.18.706531
The effect of Toxoplasma gondii infection in parental male mice on the transcriptome of their offspring’s brain
Li, Y.-N., Sun, H., Ma, J., Zhou, X.-Y., Xie, X., Xie, H., Hou, Y.-H., Dong, H., Zhao, G.-H., Xu, C., et al. (2026) · Parasites & Vectors · doi:10.1186/s13071-026-07302-7

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: Liu, Xindong
Yan, Xiaowei
Khong, Hiep
Chen, Tenghui
Huang, Rui
Wang, Xiaohu
Jin, Wei
Wang, Aibo
Nurieva, Roza
Ye, Lilin
Tian, Qiang
Bian, Xiu-Wu
Dong, Chen
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-02-27
Volume: 567
Issue: 7749
Pages: 525-529
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-0979-8
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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Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction

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