Cited by 866T-cell and B-cell ImmunologySignaling Pathways in DiseaseCancer Immunotherapy and Biomarkers

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The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells

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Martinez, Gustavo J., Pereira, Renata M., Äijö, Tarmo, Kim, Edward Y., Marangoni, Francesco, Pipkin, Matthew E., Togher, Susan, Heissmeyer, Vigo, Zhang, Yi Chen, Crotty, Shane, Lamperti, Edward D., Ansel, K. Mark, Mempel, Thorsten R., Lähdesmäki, Harri, Hogan, Patrick G., Rao, Anjana·2015·Immunity

DOI 10.1016/j.immuni.2015.01.006PMC PMC4346317

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Abstract

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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Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626591
Additional file 1 of NFAT2 overexpression suppresses the malignancy of hepatocellular carcinoma through inducing Egr2 expression
Wang, J., Zhang, Y., Liu, L., Cui, Z., Shi, R., Hou, J., Liu, Z., Yang, L., Wang, L., & Li, Y. (2020) · Figshare · doi:10.6084/m9.figshare.13059437
Self-citation
Additional file 24 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626639
Additional file 12 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626603
Additional file 26 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626645
Additional file 10 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626597
Additional file 13 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626606
Additional file 4 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626579
Additional file 16 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626615
Additional file 11 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626600
Additional file 31 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626663
Additional file 25 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626642
Additional file 23 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626636
Additional file 9 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626594
Additional file 21 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626630
Additional file 17 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626618
Additional file 3 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626576
Additional file 30 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626657
Additional file 20 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626627
Additional file 29 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626654
Additional file 14 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626609
Additional file 2 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626573
Additional file 7 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626588
Additional file 15 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626612
Additional file 19 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626624
Additional file 27 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626648
Additional file 28 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626651
Additional file 18 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626621
Additional file 6 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626585
Additional file 22 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626633
Additional file 5 of Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment
Ma, C., Yang, C., Peng, A., Sun, T., Ji, X., Mi, J., Wei, L., Shen, S., & Feng, Q. (2024) · Figshare · doi:10.6084/m9.figshare.26626582
Alternative signaling pathways for regulation of programmed cell death 1 protein expression in T lymphocytes
Batorov, E. V., Vasilchenko, P. V., & Chernykh, E. R. (2025) · Advances in molecular oncology · doi:10.17650/2313-805x-2025-12-4-73-80
PI3Kδ promotes T cell effector differentiation and plasticity during chronic infectionPreprint
Pichler, A., Cannons, J. L., Golec, D. P., Reilley, J. M., Corral, D., Ansaldo, E., Xu, Q., Paul, S., Schaughency, P., Otaizo-Carrasquero, F. A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.19.695585
CCDC97 is a Promising Predictor in Cancer Diagnosis: A Pan Cancer Analysis
Yang, C., Yang, R., Wang, R., Ma, G., & Hua, L. (2026) · Analytical Cellular Pathology · doi:10.1155/ancp/2230769
“IL-10 and enhanced TGF-β signaling have been demonstrated to contribute CD8 T cell depletion [43 – 45], which has been proven in BRCA and SKCM [46, 47].”
Transcriptional and Epigenetic Regulation of T Cell States in Cancer
Ma, S., Hargreaves, D. C., & Kaech, S. M. (2026) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061325-042744
Efficacy of FOXP3+Treg cells combined with platelet in predicting recurrence of cervical cancer: a retrospective study
Min, S., Xie, L., Wu, Y., Bo, L., Liu, Y., Zhu, Y., & Tan, Y. (2026) · BMC Women s Health · doi:10.1186/s12905-026-04274-9
“The binding of NFAT to the PD-1 promoter induces the expression of Pdcd1 (encoding PD-1) [50, 51].”
Silencing JNK Potentiates CAR-T Cell–Mediated Tumor Killing by Augmenting NFATc1-Driven Transcriptional Programs in Preclinical Ovarian Cancer Models
Martins, H. S., Teixeira, A. R., Johnson, D. M., & Williams, E. R. (2021) · Archive of International Journal of Cancer and Allied Science · doi:10.51847/8gpm3qli9r
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

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: Pereira, Renata M.
Äijö, Tarmo
Kim, Edward Y.
Marangoni, Francesco
Pipkin, Matthew E.
Heissmeyer, Vigo
Crotty, Shane
Lamperti, Edward D.
Ansel, K. Mark
Mempel, Thorsten R.
Lähdesmäki, Harri
Hogan, Patrick G.
Rao, Anjana
Venue: Immunity
Publisher: Elsevier BV
Published: 2015-02
Volume: 42
Issue: 2
Pages: 265-278
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2015.01.006
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 381 d)
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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The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells

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