The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
Open accessAbstract
Exhausted CD8+ T (T ex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (T eff) or memory (T mem) CD8+ T cells. T ex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, T ex cells are a distinct immune subset, with a unique chromatin landscape compared with T eff and T mem cells. However, the mechanisms that govern the transcriptional and epigenetic development of T ex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of T ex cells in mice. TOX is largely dispensable for the formation of T eff and T mem cells, but it is critical for exhaustion: in the absence of TOX, T ex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in T ex cells. Robust expression of TOX therefore results in commitment to T ex cells by translating persistent stimulation into a distinct T ex cell transcriptional and epigenetic developmental program.
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“which transcriptionally and epigenetically programs CD8+ T cell exhaustion [52].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [52]
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“Treatment‐induced declines in PD‐1+ CD8 T cells are consistent with the possibility that thymus regeneration treatment epigenetically reprograms “exhausted” CD8 T cells (T EX), a recently characterized distinct PD‐1+ CD8 population (Khan et al., 2019).”
From Reversal of epigenetic aging and immunosenescent trends in humans. (2019) · cites this paper as Khan et al., 2019
In the citing paper
“The excessive antigen density and kinetics of antigen exposure in solid tumors can drive exhaustion or dysfunction of T cells (Khan et al., 2019; Wherry, 2011).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Khan et al., 2019
In the citing paper
“Furthermore, bulk RNA-seq analysis of isolated cells (ND naïve, HFHC Tem, HFHC Trm, and RES Trm) revealed that both Trm subsets from HFHC mice and RES mice expressed core signature genes of Trm21–24 with exceptions including Itgae (CD103) and Eomes (Fig. 4d).”
From CD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells (2021) · cites this paper as [24]
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“CD8 T cells are typically regarded as a uniform population with cytotoxic function; however, recent studies have highlighted the diversity of the CD8 T-cell population (5)(6)(7)(8)(9).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [5]
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Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Control of Regulatory T Cell Development by the Transcription Factor Foxp3
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003) · Nature Immunology · doi:10.1038/ni904 · Cited by 7,745
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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
Self-citationMaster Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
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Restoring function in exhausted CD8 T cells during chronic viral infection
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Self-citationSuper-enhancers in the control of cell identity and disease
Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-André, V., Sigova, A. A., Hoke, H. A., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.09.053 · Cited by 3,662
Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing
Zheng, C., Zheng, L., Yoo, J.-K., Guo, H., Zhang, Y., Guo, X., Kang, B., Hu, R., Huang, J. Y., Zhang, Q., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.035 · Cited by 2,152
Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function
Zajac, A. J., Blattman, J. N., Murali-Krishna, K., Sourdive, D. J. D., Suresh, M., Altman, J. D., & Ahmed, R. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.12.2205 · Cited by 1,978
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Items 1,001–1,001 of 1,001
Yuan, Z., Liu, Z., Zhou, M., Wen, H., & Li, B. (2026) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.105111 · Cited by 6
Metadata
- Authors
- Khan, O., Giles, J. R., McDonald, S., Manne, S., Ngiow, S. F., Patel, K. P., Werner, M. T., Huang, A. C., Alexander, K. A., Wu, J. E., Attanasio, J., Yan, P., George, S. M., Bengsch, B., Staupe, R. P., Donahue, G., Xu, W., Amaravadi, R. K., Xu, X., Karakousis, G. C., Mitchell, T. C., Schuchter, L. M., Kaye, J., Berger, S. L., & Wherry, E. J.
- Affiliations
- Arsenal Biosciences (United States) (US)
- University of Pennsylvania (US)
- University of Freiburg (DE)
- Abramson Cancer Center (US)
- Cedars-Sinai Medical Center (US)
- Parker Institute for Cancer Immunotherapy (US)
- Corresponding author
- Wherry, E. John
- ORCID
- Khan, Omar
- Giles, Josephine R.
- McDonald, Sierra
- Manne, Sasikanth
- Ngiow, Shin Foong
- Patel, Kunal P.
- Werner, Michael T.
- Huang, Alexander C.
- Alexander, Katherine A.
- Wu, Jennifer E.
- Attanasio, John
- Yan, Patrick
- Bengsch, Bertram
- Staupe, Ryan P.
- Donahue, Greg
- Xu, Wei
- Amaravadi, Ravi K.
- Xu, Xiaowei
- Karakousis, Giorgos C.
- Mitchell, Tara C.
- Schuchter, Lynn M.
- Kaye, Jonathan
- Berger, Shelley L.
- Wherry, E. John
- Venue
- Nature
- Published
- 2019-06-17
- Volume
- 571
- Issue
- 7764
- Pages
- 211-218
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6713202
- OpenAlex
- W2952815301
- Cited by
- 1,646
- References
- 63
- Citations by year
- 2026: 258 · 2025: 249 · 2024: 234 · 2023: 252 · 2022: 211 · 2021: 235 · 2020: 161 · 2019: 43
- FWCI
- 64.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (R01CA078831, F32CA221010, P30CA010815, P01CA210944)
- National Institute of Allergy and Infectious Diseases (R01AI115712, R01AI054977, R01AI105343, F30AI129263, U19AI117950, U19AI082630, P01AI108545)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- TOX transcription factor, CD8+ T cell exhaustion, chromatin landscape, epigenetic regulation, calcineurin, NFATc1, feed-forward loop, inhibitory receptors, chronic infection, cancer immunotherapy, checkpoint blockade, transcriptional programs
- MeSH terms
- Animals, Epistasis, Genetic, Female, Gene Expression Regulation, Genotype, Immunologic Memory, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Transcription, Genetic, Homeodomain Proteins, CD8-Positive T-Lymphocytes, Tumor Escape, Calcineurin, Calcium Signaling, Feedback, Physiological, NFATC Transcription Factors, Mice
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