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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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Cites
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InfluentialRestoring function in exhausted CD8 T cells during chronic viral infection
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InfluentialTRANSCRIPTION FACTORS OF THE NFAT FAMILY:Regulation and Function
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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×
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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×
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Transcriptional regulation by calcium, calcineurin, and NFAT
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“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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Self-citationSingle-nucleus transcriptomics decodes the link between aging and lumbar disc herniation
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“However, in the HCC mouse model, 27 Akt1-OE CTLs exhibited delayed effector function compared with Akt2-OE CTLs and failed to eliminate tumor cells initially.”
“Dissecting the role of T cell exhaustion in cancer progression: a multifaceted approach“
Li, X., & Song, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1646292 · Cited by 12
“On the other hand, when AP-1 is absent, “ unpartnered ” NFAT binds to target genes with low transcriptional activation potential, leading to T-cell exhaustion or anergy (121, 124, 125).”
T Peripheral Helper Cells in Lymphoid Aggregate and Tertiary Lymphoid Structure Formation
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“…elucidated; however, it is clear that both Tph cells and exhausted T cells (in cancer/chronic viral infection) have downregulation of traditional AP-1 proteins, such as JUN, which limits their ability to activate canonical AP- 1-and NFAT-related pathways upon repeated stimulation [27, 40, 41].”
Regulation and Immunotherapeutic Targeting of the Epigenome in Exhausted CD8 T Cell Responses
Ford, B. R., & Poholek, A. C. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200681 · Cited by 9
CD8 is down(regulated) for tolerance
Rodríguez‐Rodríguez, N., Rosetti, F., & Crispín, J. C. (2024) · Trends in Immunology · doi:10.1016/j.it.2024.04.012 · Cited by 10
Genetic loss of NFAT2 (NFATc1) impairs B cell development of B1 and B2 B cells
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Zhang, Y., Wu, J., Zeng, C., Xu, L., Wei, W., & Li, Y. (2021) · Immunobiology · doi:10.1016/j.imbio.2021.152111 · Cited by 9
Self-citationRapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9+ T Cells
Majumder, S., Jugovic, I., Saul, D., Bell, L., Hundhausen, N., Seal, R., Beilhack, A., Rosenwald, A., Mougiakakos, D., & Berberich‐Siebelt, F. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.683631 · Cited by 9
Devi, P., Ota, S., Punga, T., & Bergqvist, A. (2021) · Viruses · doi:10.3390/v13122514 · Cited by 9
“The Ca2+ efflux in turn upregulates the proximal signaling by inducing anergy-associated genes including soluble and receptor tyrosine phosphatases [20,21].”
BackgroundEvolving Views of Long Noncoding RNAs and Epigenomic Control of Lymphocyte State and MemoryPreprint
Morrison, T. A., Hudson, W. H., Chisolm, D. A., Kanno, Y., Shih, H., Ahmed, R., Henao‐Mejia, J., Hafner, M., & O’Shea, J. J. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a037952 · Cited by 9
NFAT signaling is indispensable for persistent memory responses of MCMV-specific CD8+ T cells
Chaudhry, M. Z., Borkner, L., Kulkarni, U., Berberich‐Siebelt, F., & Čičin‐Šain, L. (2024) · PLoS Pathogens · doi:10.1371/journal.ppat.1012025 · Cited by 8
“Nfat2 (NFATc1c2 DKO) animals have been described before (31, 34, 35).”
BackgroundWu, B., Koehler, A. N., & Westcott, P. M. K. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.08.002 · Cited by 9
Mai, L. T., Swaminathan, S., Nguyen, T. H., Collette, É., Charpentier, T., Carmona‐Pérez, L., Loucif, H., Lamarre, A., Heinonen, K. M., Langlais, D., et al. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00485-2 · Cited by 8
“Members of Nuclear factor of activated T cells (NFAT) family of transcription factors regulate the expression of inhibitory receptors thus promoting the Tex phenotype (Martinez et al, 2015; Oestreich et al, 2008).”
Enhancing the potency of CAR-T cells against solid tumors through transcription factor engineering
Chen, R., Chen, L., Tang, Y. R., Xiaolin, S., Wang, Y., Tang, P., Shentu, X., & Sun, J. (2025) · JCI Insight · doi:10.1172/jci.insight.193048 · Cited by 9
Zhao, R., Zhang, J., Zhang, S., Schwarz, E. C., del Campo, A., Hoth, M., & Qu, B. (2026) · Science Signaling · doi:10.1126/scisignal.adt9566 · Cited by 8
Feeling Exhausted? Tuning Irf4 Energizes Dysfunctional T Cells
Chennupati, V., & Held, W. (2017) · Immunity · doi:10.1016/j.immuni.2017.11.028 · Cited by 8
“…deficiencies lead to a corresponding reversal of CD8+ T cell exhaustion (Man et al., 2017), which is similar to earlier NFAT loss-of-function experiments (Martinez et al., 2015), indicating that CD8+ T cell exhaustion is driven by the co-operation of a set of TCR-responsive transcription factors.”
ResultCatherinet, C., Passaro, D., Gachet, S., Medyouf, H., Reynaud-Angelin, A., Lasgi, C., Ghysdael, J., & Quang, C. T. (2021) · PLoS ONE · doi:10.1371/journal.pone.0254184 · Cited by 8
NFATc1/αA and Blimp-1 Support the Follicular and Effector Phenotype of Tregs
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“These pathways may be related via NFAT signaling (25).”
Backgroundc-Jun Overexpressing CAR-T Cells are Exhaustion-Resistant and Mediate Enhanced Antitumor ActivityPreprint
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Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer
Ojo, O. A., Shen, H., Ingram, J. T., Bonner, J. A., Welner, R. S., Lacaud, G., Zajac, A. J., & Shi, L. Z. (2025) · Nature Communications · doi:10.1038/s41467-025-59784-1 · Cited by 9
Epigenetic reprogramming holds promise in enhancing anti-tumor efficacy of CAR T cell therapy
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Epigenetic priming as a driver of memory recall and dysfunction in T cells
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CD7 regulates the persistence of terminally exhausted CD8+ T cells during chronic infection
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Immune checkpoint TIM-3 in tumor immunotherapy
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“26,29 From these observations, it was suggested that constitutive activation of NFAT is related to the exhausted phenotype of SKM-28z CAR-T cells via TOX and NR4A molecules.”
BackgroundElliot, T. A. E., Lecky, D. A. J., & Bending, D. (2023) · Essays in Biochemistry · doi:10.1042/ebc20220247 · Cited by 6
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Self-citationDysfunctional states of unconventional T-cell subsets in cancer
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Self-citationArginine-based cationic liposomes accelerate T cell activation and differentiation in vitro
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“Additional work has shown that NFAT orchestrates a program of T cell exhaustion in the absence of AP-1-binding partners (Martinez et al, 2015) through positive regulation of the TOX/NR4A T cell exhaustion axis (Chen et al, 2019; Seo et al, 2019), leading to displacement of AP-1 binding by NR4A (Liu…”
Moine, M. L., Azouz, A., Sanchez, G. S., Dejolier, S., Nguyen, M., Thomas, S., Shala, V., Dreidi, H., Denanglaire, S., Libert, F., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112876 · Cited by 8
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Co-inhibitory receptors, transcription factors and tolerance
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Charab, W., Rosenberger, M. G., Shivram, H., Mirazee, J. M., Donkor, M. K., Shekhar, S., Gjuka, D., Khoo, K. H. L., Kim, J. E., Iyer, V. R., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.713704 · Cited by 6
“IgG1 Immune Complexes Inhibit Naïve T Cell Proliferation but Stimulate a Subset of Their Progeny Well-defined immune complexes (ICs) were formed using trinitrophenol-conjugated bovine serum albumin (TNP-BSA; 25-35 TNP-moieties/BSA molecule) as the antigen and monoclonal anti-trinitrophenol antibodies to form TNP-BSAan…”
BackgroundMethodInfluentialHIV-1-Specific CD11c+ CD8+ T Cells Display Low PD-1 Expression and Strong Anti-HIV-1 Activity
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“Interestingly, unlike conventional CD8 T cells characterized by high activation along with high PD-1 expression (27), CD11c”
BackgroundFord, B. R., Rittenhouse, N., Scharping, N. E., Vignali, P., Frisch, A. T., Peralta, R. M., Delgoffe, G. M., & Poholek, A. C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.11.451947 · Cited by 6
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Self-citationLeveraging T cells for cancer immunotherapy
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“Chronic antigen stimulation and inflammatory signalling promote T cell exhaustion, an epigenetically stable, dysfunctional phenotype driven by the transcription factors thymocyte selection-associated high mobility group box (TOX) and TOX2 [88–90].”
Altshuler-Keylin, S., Caduff, N., Ishizuka, I. E., Reja, R., Nutsch, K., Gao, C., Wang, J., Kaufmann, U., Tleugabulova, M. C., Dixon, E. L., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02333-1 · Cited by 5
“This was intriguing because NFAT signaling has been implicated in the progression of T cell exhaustion 38 .”
Hoyt-Miggelbrink, A. M., Polania, J. W., Wachsmuth, L. P., Lorrey, S., Mohan, A. A., Hardigan, A. A., Blandford, E. E., Lerner, E., Wilkinson, D. S., Hotchkiss, K. M., et al. (2025) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-3455 · Cited by 6
“Interestingly, TNFR2-KO T cells displayed decreased expression of the Nfatc1 , Nfatc2 , and Nfact3 genes and increased expression of AP1 transcription factors, including Jund , Junb , Jun , Fosb , Fos , Akt1 , and Batf3 ( Fig.”
InfluentialGuo, C., Griffin, M., Morgan, A. G., Foster, D. S., Parker, J. B. L., Januszyk, M., Lindsay, H. G., Guardino, N. J., Reveron‐Thornton, R. F., Xie, P. Y., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2025.116849 · Cited by 5
Chronic TCR signaling-driven suppression of the FOXO1-KLHL6 axis promotes T cell exhaustion
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SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling
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“When unable to interact with AP-1, NFAT promotes T cell anergy and exhaustion by inducing the expression of signaling molecules that dampen TCR signaling 27 .”
Pinho, A. C. O., Barbosa, P., Lázaro, A., Tralhão, J. G., Pereira, M. J., Paiva, A. A., Laranjeira, P., & Carvalho, E. (2024) · Immunology Letters · doi:10.1016/j.imlet.2024.106911 · Cited by 5
Transcriptional rewiring in CD8+ T cells: implications for CAR-T cell therapy against solid tumours
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“For instance, AP-1/NFAT cooperation elicits downstream IL-2 and cytokine production (119), whilst NFAT activity alone drives exhaustion-like programs in CD8 + T cells (120).”
BackgroundLi, K., Lu, L., Yao, X., Wu, Z., Sun, P., Wen, X., Li, X., Wang, K., & Yin, X. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.11.014 · Cited by 5
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“The expression of inhibitory T cell receptor is related to TCR signal and indicates the activation of negative regulatory pathway (42).”
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“LAG3 transcription is regulated by several transcription factors including TOX and NFAT [37, 38].”
BackgroundHow does NFAT3 regulate the occurrence of cardiac hypertrophy?
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Unraveling T-cell Exhaustion: Genetic Screening Meets In Vitro Modeling
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“On the other hand, cellular proliferation ability is controlled also by other signaling pathways than [Ca2+]i, such as transcription factors like cAMP response element-binding protein (CREB), AP-1, and NFAT (Dolmetsch et al., 1998; Martinez et al., 2015; Shin et al., 2019).”
BackgroundExendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System
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“The calcineurin/nuclear factor of activated T cells (NFATc1) is activated upon T cell receptor activation followed by intracytoplasmatic calcium influx [57] and subsequent nuclear translocation [58].”
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Semiallogeneic Pregnancy: A Paradigm Change for T-cell Transplantation Tolerance
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Targeting the hippo pathway as a potential regulator of immune checkpoints in cancer immunotherapy
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“It has been demonstrated that CD8+ T cells can become exhausted or dysfunctional within the tumor microenvironment (TME) during CAR-T cell therapy [18,25–27].”
pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication
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Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis
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“28,29 30 – 32 In this study, we also explored the potential of using RNA expression pro fi les to predict PD-L1 status using a machine learning approach.”
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“The identification of NFATc2 binding sites as particularly effective elements for exhaustion ‐ specific promoters aligns with and extends previous studies of T cell regulation [7, 22].”
Prevention of CAR-T-cell dysfunction
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Self-citationThe Transcription Factor NFATc1 Supports the Rejection of Heterotopic Heart Allografts
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“Conversely, RUNX3 [33], EOMES [33], TBX21 [34], and NFATC2 [35] exhibited high regulatory activity in CD8 + Tcm, CD8 + Tcm_ KLRB1, and CD8 + Tem (Fig.”
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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