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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]
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“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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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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“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
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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
Blank, C. U., Haining, W. N., Held, W., Hogan, P. G., Kallies, A., Lugli, E., Lynn, R. C., Philip, M., Rao, A., Restifo, N. P., et al. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0221-9 · Cited by 1,603
Self-citationEpigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade
Pauken, K. E., Sammons, M. A., Odorizzi, P. M., Manne, S., Godec, J., Khan, O., Drake, A. M., Chen, Z., Sen, D. R., Kurachi, M., et al. (2016) · Science · doi:10.1126/science.aaf2807 · Cited by 1,348
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Overcoming T cell exhaustion in infection and cancer
Pauken, K. E., & Wherry, E. J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.02.008 · Cited by 1,220
“Moreover, NFAT binding in the absence of AP-1 appears to promote expression of some features of an exhausted transcriptional program [128].”
BackgroundTOX is a critical regulator of tumour-specific T cell differentiation
Scott, A. C., Dündar, F., Zumbo, P., Chandran, S. S., Klebanoff, C. A., Shakiba, M., Trivedi, P., Menocal, L., Appleby, H., Camara, S., et al. (2019) · Nature · doi:10.1038/s41586-019-1324-y · Cited by 1,106
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Philip, M., & Schietinger, A. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00574-3 · Cited by 1,052
Clinical implications of T cell exhaustion for cancer immunotherapy
Chow, A., Perica, K., Klebanoff, C. A., & Wolchok, J. D. (2022) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-022-00689-z · Cited by 1,044
Sun, L., Su, Y., Jiao, A., Wang, X., & Zhang, B. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01471-y · Cited by 1,153
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Sen, D. R., Kaminski, J., Barnitz, R. A., Kurachi, M., Gerdemann, U., Yates, K. B., Tsao, H.-W., Godec, J., LaFleur, M. W., Brown, F. D., et al. (2016) · Science · doi:10.1126/science.aae0491 · Cited by 986
Satpathy, A. T., Granja, J. M., Yost, K. E., Qi, Y., Meschi, F., McDermott, G. P., Olsen, B. N., Mumbach, M. R., Pierce, S. E., Corces, M. R., et al. (2019) · Nature Biotechnology · doi:10.1038/s41587-019-0206-z · Cited by 980
Chromatin states define tumour-specific T cell dysfunction and reprogramming
Philip, M., Fairchild, L., Sun, L., Horste, E. L., Camara, S., Shakiba, M., Scott, A. C., Viale, A., Lauer, P., Merghoub, T., et al. (2017) · Nature · doi:10.1038/nature22367 · Cited by 933
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Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., et al. (2019) · Nature · doi:10.1038/s41586-019-1805-z · Cited by 891
Scharping, N. E., Rivadeneira, D. B., Menk, A. V., Vignali, P. D. A., Ford, B. R., Rittenhouse, N. L., Peralta, R., Wang, Y., Wang, Y., DePeaux, K., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00834-9 · Cited by 897
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Alfei, F., Kanev, K., Hofmann, M., Wu, M., Ghoneim, H. E., Roelli, P., Utzschneider, D. T., von Hoesslin, M., Cullen, J. G., Fan, Y., et al. (2019) · Nature · doi:10.1038/s41586-019-1326-9 · Cited by 930
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Chen, J., López-Moyado, I. F., Seo, H., Lio, C.-W. J., Hempleman, L. J., Sekiya, T., Yoshimura, A., Scott-Browne, J. P., & Rao, A. (2019) · Nature · doi:10.1038/s41586-019-0985-x · Cited by 874
Self-citationSeo, H., Chen, J., González-Avalos, E., Samaniego-Castruita, D., Das, A., Wang, Y. H., López-Moyado, I. F., Georges, R. O., Zhang, W., Onodera, A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1905675116 · Cited by 808
“We also examined cells expressing CA-RIT-NFAT1, a constitutively active version of NFAT1 that cannot interact with AP-1 (19, 20); CA-RIT-NFAT1 induces a transcriptional program very similar to exhaustion both in vitro and in vivo (20, 21), whereas another mutated version of CA-RIT-NFAT1 that cannot bind DNA (DBD mut)…”
BackgroundSelf-citationCDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation
Deng, J., Wang, E. S., Jenkins, R. W., Li, S., Dries, R., Yates, K., Chhabra, S., Huang, W., Liu, H., Aref, A. R., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0915 · Cited by 770
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialSelf-citationTCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision
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Speiser, D. E., Ho, P., & Verdeil, G. (2016) · Nature reviews. Immunology · doi:10.1038/nri.2016.80 · Cited by 570
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Liu, X., Wang, Y., Lu, H., Li, J., Yan, X., Xiao, M., Hao, J., Alekseev, A., Khong, H., Chen, T., et al. (2019) · Nature · doi:10.1038/s41586-019-0979-8 · Cited by 533
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Bunse, L., Pusch, S., Bunse, T., Sahm, F., Sanghvi, K., Friedrich, M., Alansary, D., Sonner, J. K., Green, E., Deumelandt, K., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0095-6 · Cited by 561
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Man, K., Gabriel, S. S., Liao, Y., Gloury, R., Preston, S., Henstridge, D. C., Pellegrini, M., Zehn, D., Berberich‐Siebelt, F., Febbraio, M. A., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.11.021 · Cited by 503
Huang, Q., Wu, X., Wang, Z., Chen, X., Wang, L., Lu, Y., Xiong, D., Liu, Q., Tian, Y., Lin, H., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.020 · Cited by 486
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Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells
Odorizzi, P. M., Pauken, K. E., Paley, M., Sharpe, A. H., & Wherry, E. J. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20142237 · Cited by 480
“CD8+ TEX cells also have altered expression of key transcription factors, including Tbet, Eome sodermin (Eomes), FoxO1, and others (Shin et al., 2009; Kao et al., 2011; Paley et al., 2012; Staron et al., 2014; Martinez et al., 2015).”
BackgroundPrecursor exhausted T cells: key to successful immunotherapy?
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BackgroundT‐cell exhaustion in HIV infection
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Self-citationPD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy?
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“described NFATs as an early transcriptional checkpoint progressively driving exhaustion.(25)”
BackgroundHuang, R., Francois, A., McGray, A. R., Miliotto, A. J., & Odunsi, K. O. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1249561 · Cited by 395
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Elyahu, Y., Hekselman, I., Eizenberg-Magar, I., Berner, O., Strominger, I., Schiller, M., Mittal, K., Nemirovsky, A., Eremenko, E., Vital, A., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw8330 · Cited by 324
Saeidi, A., Zandi, K., Cheok, Y. Y., Saeidi, H., Wong, W. F., Lee, C. Y. Q., Cheong, H. C., Yong, Y. K., Larsson, M., & Shankar, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02569 · Cited by 361
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“Likewise, the transcription factor nuclear factor of activated T cells (NFAT), downstream of Zap70, plays a primary role in both exhaustion and adaptive tolerance (85).”
BackgroundEarly precursor T cells establish and propagate T cell exhaustion in chronic infection
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Mognol, G. P., Spreafico, R., Wong, V., Scott-Browne, J. P., Togher, S., Hoffmann, A., Hogan, P. G., Rao, A., & Trifari, S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620498114 · Cited by 324
“5C) (28, 38), NFAT may set up the accessibility of this region in exhausted cells, potentially paving the way for Nr4a and other transcription factors to bind the region and maintain its accessibility.”
BackgroundMethodInfluentialSelf-citationDynamic Changes in Chromatin Accessibility Occur in CD8 + T Cells Responding to Viral Infection
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Self-citationAP-1 Transcription Factors as Regulators of Immune Responses in Cancer
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Ma, C., Yang, C., Peng, A. F., Sun, T., Ji, X., Mi, J., Li, W., Shen, S., & Feng, Q. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01876-x · Cited by 295
“Notably, we identified nuclear factor of activated T cells 1 and 2 (NFATC1 and NFATC2) in the intracellular signaling network triggered by LGALS1-PTPRC interaction (Figure S18a), which are considered as key transcription factors (TFs) leading to CD8 + T cells exhaustion [39, 40].”
BackgroundStore-Operated Ca2+ Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming
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“Deletion of NFATc1 and NFATc2 in T cells strongly impaired glycolytic gene expression, whereas expression of constitutively active NFATc1 in SOCE-deficient T cells restored glycolysis and T cell proliferation in vivo.”
InfluentialUnique immunological profile in patients with COVID-19
Varchetta, S., Mele, D., Oliviero, B., Mantovani, S., Ludovisi, S., Cerino, A., Bruno, R., Castelli, A., Mosconi, M., Vecchia, M., et al. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00557-9 · Cited by 282
Grabowski, M. M., Sankey, E. W., Ryan, K. J., Chongsathidkiet, P., Lorrey, S., Wilkinson, D. S., & Fecci, P. E. (2020) · Journal of Neuro-Oncology · doi:10.1007/s11060-020-03483-y · Cited by 270
“While in the exhausted state, failure of NFAT to form a complex with AP-1 results in expression of inhibitory immune checkpoints, such as PD-1 and CTLA-4 [18].”
BackgroundChallenges and new technologies in adoptive cell therapy
Zhang, P., Zhang, G., & Wan, X. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01492-8 · Cited by 291
Effector, Memory, and Dysfunctional CD8+T Cell Fates in the Antitumor Immune Response
Reiser, J., & Banerjee, A. (2016) · Journal of Immunology Research · doi:10.1155/2016/8941260 · Cited by 262
“NFAT regulates the expression of PD-1 and Tim-3 and thus may contribute to CD8 + T cell exhaustion in chronic viral infection and cancer [139].”
Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease
Attanasio, J., & Wherry, E. J. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.022 · Cited by 267
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
Yates, K. B., Tonnerre, P., Martin, G. E., Gerdemann, U., Abosy, R. A., Comstock, D. E., Weiss, S. A., Wolski, D., Tully, D. C., Chung, R. T., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-00979-1 · Cited by 257
Okada, M., Chikuma, S., Kondo, T., Hibino, S., Machiyama, H., Yokosuka, T., Nakano, M., & Yoshimura, A. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.027 · Cited by 257
Hochrein, S. M., Wu, H., Eckstein, M., Arrigoni, L., Herman, J. S., Schumacher, F., Gerecke, C., Rosenfeldt, M. T., Grün, D., Kleuser, B., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.015 · Cited by 253
Kim, C. G., Jang, M., Kim, Y., Leem, G., Kim, K. H., Lee, H., Kim, T.-S., Choi, S. J., Kim, H.-D., Han, J. W., et al. (2019) · Science Immunology · doi:10.1126/sciimmunol.aay0555 · Cited by 245
Androgen conspires with the CD8 + T cell exhaustion program and contributes to sex bias in cancer
Kwon, H., Schafer, J. M., Song, N., Kaneko, S., Li, A., Xiao, T., Ma, A., Allen, C., Das, K., Zhou, L., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abq2630 · Cited by 254
Cellular networks controlling T cell persistence in adoptive cell therapy
Chan, J. D., Lai, J., Slaney, C. Y., Kallies, A., Beavis, P. A., & Darcy, P. K. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00539-6 · Cited by 253
RASA2 ablation in T cells boosts antigen sensitivity and long-term function
Carnevale, J. C., Shifrut, E., Kale, N., Nyberg, W. A., Blaeschke, F., Chen, Y. Y., Li, Z., Bapat, S. P., Diolaiti, M. E., O’Leary, P. C., et al. (2022) · Nature · doi:10.1038/s41586-022-05126-w · Cited by 243
Memory T cell, exhaustion, and tumor immunity
Ando, M., Ito, M., Srirat, T., Kondo, T., & Yoshimura, A. (2019) · Immunological Medicine · doi:10.1080/25785826.2019.1698261 · Cited by 233
“T cell exhaustion has been studied using the following three models: chronic viral infections such as lymphocytic choriomeningitis virus (LCMV) [21], tumor models, and overexpression of NFAT1 (nuclear factor of activated T cells-1) without AP1binding site [22].”
Method‘Stem-like’ precursors are the fount to sustain persistent CD8+ T cell responses
Zehn, D., Thimme, R., Lugli, E., de Almeida, G. P., & Oxenius, A. (2022) · Nature Immunology · doi:10.1038/s41590-022-01219-w · Cited by 232
Divergent clonal differentiation trajectories of T cell exhaustion
Dániel, B., Yost, K. E., Hsiung, S., Sándor, K., Xia, Y., Qi, Y., Hiam-Galvez, K. J., Black, M., Raposo, C. J., Shi, Q., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01337-5 · Cited by 241
T cell Allorecognition Pathways in Solid Organ Transplantation
Siu, J. H. Y., Surendrakumar, V., Richards, J. A., & Pettigrew, G. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02548 · Cited by 223
“Finally, although exhausted T cells exhibit typical aerobic glycolysis at initiation of the response, continued antigen binding to the TCR results in downregulation of the PI3K–AKT1–mTOR signaling pathway (139) and NFATC-mediated expression of PD-1 and other inhibitory ligands (140, 141).”
BackgroundStem-like exhausted and memory CD8+ T cells in cancer
Gebhardt, T., Park, S. L., & Parish, I. A. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00615-0 · Cited by 223
“Chronic antigen recognition is the primary factor that triggers exhausted CD8 + T cell differentiation via chronic nuclear factor of activated T cells (NFAT) transcription factor activation downstream of T cell receptor (TCR)-induced calcium flux 285 .”
BackgroundWilliams, J. B., Horton, B. L., Zheng, Y., Duan, Y., Powell, J. D., & Gajewski, T. F. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20160485 · Cited by 213
In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer
Chen, Z., Arai, E., Khan, O., Zhang, Z., Ngiow, S. F., He, Y. M., Huang, H., Manne, S., Cao, Z., Baxter, A. E., et al. (2021) · Cell · doi:10.1016/j.cell.2021.02.019 · Cited by 210
“We also identified Nfatc2 and Nr4a2 (Figure 1C), both of which have been implicated in fostering T cell exhaustion and thus limiting TEFF responses (Chen et al., 2019a; Martinez et al., 2015).”
Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor
Zhang, J., Li, J., Hou, Y., Lin, Y., Zhao, H., Shi, Y., Chen, K., Nian, C., Tang, J., Pan, L., et al. (2024) · Cell · doi:10.1016/j.cell.2024.04.023 · Cited by 214
Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop
Marangoni, F., Zhakyp, A., Corsini, M., Geels, S. N., Carrizosa, E., Thelen, M., Mani, V., Pruessmann, J. N., Warner, R. D., Ozga, A. J., et al. (2021) · Cell · doi:10.1016/j.cell.2021.05.027 · Cited by 209
Self-citationNFATc1 controls the cytotoxicity of CD8+ T cells
Klein‐Hessling, S., Muhammad, K., Klein, M., Pusch, T., Rudolf, R., Flöter, J., Qureischi, M., Beilhack, A., Vaeth, M., Kummerow, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00612-6 · Cited by 202
Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker
Wang, Z., & Wu, X. (2020) · Cancer Medicine · doi:10.1002/cam4.3410 · Cited by 203
Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development
Tang, L., Pan, S. D., Wei, X., Xu, X., & Wei, Q. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.09.021 · Cited by 209
Activation or exhaustion of CD8+ T cells in patients with COVID-19
Rha, M., & Shin, E. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00750-4 · Cited by 201
NFAT control of immune function: New Frontiers for an Abiding Trooper
Vaeth, M., & Feske, S. (2018) · F1000Research · doi:10.12688/f1000research.13426.1 · Cited by 191
Gabriel, S. S., Tsui, C., Chisanga, D., Weber, F., Llano-León, M., Gubser, P. M., Bartholin, L., Souza-Fonseca-Guimarães, F., Huntington, N. D., Shi, W., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.06.007 · Cited by 200
Taylor, A., Harker, J. A., Chanthong, K., Stevenson, P. G., Zúñiga, E. I., & Rudd, C. E. (2016) · Immunity · doi:10.1016/j.immuni.2016.01.018 · Cited by 197
“Pdcd1 expression is regulated by NFAT2 (Oestreich et al., 2008) and NFAT binding sites exist inTbx21 (Martinez et al., 2015).”
InfluentialGuedan, S., Madar, A., Casado‐Medrano, V., Shaw, C. E., Wing, A., Liu, F., Young, R. M., June, C. H., & Posey, A. D. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133215 · Cited by 190
“associated with overactivation of NFAT to produce “partnerless NFAT”, which has been shown to drive T cells into states of exhaustion and dysfunction, specifically through the upregulation of NR4A transcription factors and TOX (28, 29).”
BackgroundDysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism
Peralta, R. M., Xie, B., Lontos, K., Nieves-Rosado, H. M., Spahr, K., Joshi, S. K., Ford, B. R., Quann, K., Frisch, A. T., Dean, V. G., et al. (2024) · Nature Immunology · doi:10.1038/s41590-024-01999-3 · Cited by 211
Calcium–NFAT transcriptional signalling in T cell activation and T cell exhaustion
Hogan, P. G. (2017) · Cell Calcium · doi:10.1016/j.ceca.2017.01.014 · Cited by 188
“RNA sequencing shows that both the activation and the unresponsiveness gene programs are invoked simultaneously during T cell activation [18,23].”
BackgroundInfluentialSelf-citationChronic stimulation drives human NK cell dysfunction and epigenetic reprograming
Merino, A. M., Zhang, B., Dougherty, P., Luo, X., Wang, J., Blazar, B. R., Miller, J. S., & Cichocki, F. M. (2019) · Journal of Clinical Investigation · doi:10.1172/jci125916 · Cited by 197
Wang, D., Prager, B. C., Gimple, R. C., Aguilar, B., Alizadeh, D., Tang, H., Lv, D., Starr, R., Brito, A., Wu, Q., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1243 · Cited by 185
LAG3’s Enigmatic Mechanism of Action
Graydon, C. G., Mohideen, S., & Fowke, K. R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.615317 · Cited by 183
“This prevents activation of transcription factors, including NFAT, thereby decreasing cytokine production and proliferation.”
BackgroundThe function and dysfunction of memory CD 8+ T cells in tumor immunity
Reading, J. L., Gálvez‐Cancino, F., Swanton, C., Lladser, Á., Peggs, K. S., & Quezada, S. A. (2018) · Immunological Reviews · doi:10.1111/imr.12657 · Cited by 185
Chen, Y., Zander, R., Wu, X., Schauder, D., Kasmani, M. Y., Shen, J., Zheng, S., Burns, R., Taparowsky, E. J., & Cui, W. (2021) · Nature Immunology · doi:10.1038/s41590-021-00965-7 · Cited by 183
Hu, J., Chen, Z., Bao, L., Zhou, L., Hou, Y., Liu, L., Xiong, M., Zhang, Y., Wang, B., Tao, Z., et al. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.04.023 · Cited by 183
Self-citationPSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion
Tinoco, R., Carrette, F., Henriquez, M. L., Otero, D. C., Magaña, J., Bosenberg, M., Swain, S. L., & Bradley, L. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.015 · Cited by 179
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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