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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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“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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“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
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“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
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“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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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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