The DOI matches its Crossref record; 52 of the 52 references it cites were found in a registry or an index.
The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells
Open accessAbstract
During persistent antigen stimulation, CD8(+) T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8(+) T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8(+) T cells and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8(+) T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.
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“Exhausted cells presented a high activity of Nfatc1 regulon, which is presumably involved in regulating the exhaustion process (50–53).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [51]
In the citing paper
“TCR-induced Ca2+–NFAT signaling is indispensable for T cell exhaustion and induces the expression of inhibitory surface receptors, such as PD-1, Lag-3 and Tim-3 (ref. 43).”
From Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma (2023) · cites this paper as [43]
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Citations
Cites
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · cited 1×
“Barcoded librarieswere sequenced in aSOLID4 sequencer (Applied Biosystems) and the reads were mapped by Bowtie (Langmead et al., 2009) to the mm9 genome in color-space.”
Calcium's Role in Mechanotransduction during Muscle Development
Damm, T. B., & Egli, M. (2014) · Cellular Physiology and Biochemistry · doi:10.1159/000356667 · Cited by 14,552
TopHat: discovering splice junctions with RNA-Seq
Trapnell, C., Pachter, L. S., & Salzberg, S. L. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp120 · Cited by 11,682
Wherry, E. J. (2011) · Nature Immunology · doi:10.1038/ni.2035 · Cited by 4,062 · cited 15×
“, 2011), and in CD8 T cells in the context of prolonged low-grade antigenic stimulation and/or inflammation, as encountered in chronic viral infections and cancer (Schietinger and Greenberg, 2014; Wherry, 2011).”
InfluentialRestoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057 · cited 4×
“, 2006), and blocking this pathway during chronic LCMV infection reinvigorates virus-specific CD8 T cell responses, resulting in lower viral loads (Barber et al., 2006).”
InfluentialTRANSCRIPTION FACTORS OF THE NFAT FAMILY:Regulation and Function
Rao, A., Luo, C. H., & Hogan, P. G. (1997) · Annual Review of Immunology · doi:10.1146/annurev.immunol.15.1.707 · Cited by 2,592 · cited 2×
“Notably, most NFAT1 ChIP-seq peaks did not overlap with CARIT-NFAT1 ChIP-seq peaks (Figure 4A, left and middle), suggesting that at these sites, NFAT binding is strongly stabilized by AP-1 (probably by 20-fold ormore) (Rao et al., 1997).”
Self-citationMolecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103 · cited 14×
“…in CD8+ and CD4+ T cells by CA-RIT-NFAT1 and those observed in exhausted CD8+ T cells and anergic CD4+ T cells in vivo (22/56 genes and 99/371 genes, respectively; p value < 10 10) (Figures 2E, 2F, and S3E; Tables 1, S1, and S2; Doering et al., 2012; Okamura et al., 2009; Wherry et al., 2007).”
InfluentialTargeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K., & Anderson, A. C. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20100643 · Cited by 2,072 · cited 2×
“Moreover, antibodies to PD-1 and CTLA-4 have emerged as surprisingly effective agents for cancer immunotherapy (Schietinger and Greenberg, 2014), and individual or combined blockade of TIM3, PD-1, and LAG3 with antagonist antibodies has been shown to reverse exhaustion efficiently in CD8 T cells (Blackburn et al., 200…”
Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R., Freeman, G. J., Vignali, D. A. A., & Wherry, E. J. (2009) · Nature Immunology · doi:10.1038/ni.1679 · Cited by 2,062 · cited 2×
“Moreover, antibodies to PD-1 and CTLA-4 have emerged as surprisingly effective agents for cancer immunotherapy (Schietinger and Greenberg, 2014), and individual or combined blockade of TIM3, PD-1, and LAG3 with antagonist antibodies has been shown to reverse exhaustion efficiently in CD8 T cells (Blackburn et al., 200…”
Transcriptional regulation by calcium, calcineurin, and NFAT
Hogan, P. G., Chen, L., Nardone, J., & Rao, A. (2003) · Genes & Development · doi:10.1101/gad.1102703 · Cited by 1,991 · cited 3×
“The ability to participate inmultiple transcriptional complexes allows NFAT to contribute to different transcriptional programs depending on the cell type and signaling context in which it is activated (Hogan et al., 2003).”
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Cited by
Sorted by citations
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., et al. (2016) · Science · doi:10.1126/science.aad0501 · Cited by 4,944
“Another variable gene of interest was the transcription factor NFATC1; previously implicated in T cell exhaustion (49).”
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
Miller, B. C., Sen, D. R., Al Abosy, R., Bi, K., Virkud, Y. V., LaFleur, M. W., Yates, K. B., Lako, A., Felt, K., Naik, G. S., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0312-6 · Cited by 2,087
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 2,054
“NFAT is a family of transcription factors with well-established roles in T cell activation (261, 262), T cell anergy (263), and T cell exhaustion (7, 9, 122).”
BackgroundInfluentialTOX transcriptionally and epigenetically programs CD8+ T cell exhaustion
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., et al. (2019) · Nature · doi:10.1038/s41586-019-1325-x · Cited by 1,646
Metadata
- Authors
- 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., Lamperti, E. D., Ansel, K. M., Mempel, T. R., Lähdesmäki, H., Hogan, P. G., & Rao, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- Harvard University (US)
- Scripps Research Institute (US)
- Helmholtz Munich (DE)
- St. Luke's-Roosevelt Hospital Center (US)
- Boston Children's Hospital (US)
- University of California, San Francisco (US)
- Aalto University (FI)
- Corresponding author
- Lähdesmäki, Harri
- Rao, Anjana
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 42
- Issue
- 2
- Pages
- 265-278
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC4346317
- OpenAlex
- W2018775174
- Cited by
- 857
- References
- 52
- Citations by year
- 2026: 104 · 2025: 97 · 2024: 110 · 2023: 104 · 2022: 84 · 2021: 95 · 2020: 84 · 2019: 69 · 2018: 30 · 2017: 37 · 2016: 26 · 2015: 17
- FWCI
- 18.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- National Cancer Institute (R01CA150975, U19CA179563, R01CA042471, R01 CA-42471)
- National Institute of Allergy and Infectious Diseases (R01 AI40127, R01AI072543, R01AI095634, AI84167, U19AI109976, R01AI084167, R01AI109842, R01AI040127)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK043351)
- National Center for Research Resources (S10RR027366)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- NFAT1, T cell exhaustion, CD8+ T cells, T cell anergy, T cell receptor signaling, AP-1, inhibitory receptors, listeriosis, antitumor immunity, transcriptional regulation
- MeSH terms
- Animals, Cells, Cultured, Gene Expression Regulation, Listeriosis, Listeria monocytogenes, Lymphocyte Activation, Mice, Transgenic, Neoplasms, Promoter Regions, Genetic, Receptors, Antigen, T-Cell, Recombinant Proteins, Clonal Anergy, CD8-Positive T-Lymphocytes, Transcription Factor AP-1, NFATC Transcription Factors, Mice
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