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 high activity of Nfatc1 regulon, presumably involved in regulating the exhaustion process.
“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]
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.
“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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InfluentialTRANSCRIPTION FACTORS OF THE NFAT FAMILY:Regulation and Function
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InfluentialTargeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity
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InfluentialNFAT proteins: key regulators of T-cell development and function
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Self-citationCooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection
Jin, H.-T., Anderson, A. C., Tan, W. G., West, E. E., Ha, S.-J., Araki, K., Freeman, G. J., Kuchroo, V. K., & Ahmed, R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009731107 · Cited by 858 · cited 4× · see citing works
“…its versatility, NFAT forms dimers on palindromic kB-like sequence elements and can bind DNA as a monomer (Chen et al., 1998; Giffin et al., 2003; Jin et al., 2010; Stroud et al., 2002); it also forms cooperative complexes with FOXP3, a transcription factor central to T cell regulatory function…”
InfluentialPipkin, M. E., Sacks, J. A., Cruz‐Guilloty, F., Lichtenheld, M. G., Bevan, M. J., & Rao, A. (2010) · Immunity · doi:10.1016/j.immuni.2009.11.012 · Cited by 799 · cited 7× · see citing works
“When differentiated into ‘‘memory’’ CTLs (Pipkin et al., 2010) and restimulated with PMA and ionomycin in vitro, NFAT1,2 double-deficient CD8+ T cells showed clearly decreased induction of the effector cytokines IL-2 and IFN-g compared toWT or singly NFAT1- or NFAT2-deficient CD8+ T cells (Figure 5A); they also showed…”
InfluentialSelf-citationThe T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun
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Self-citationTranscriptional Mechanisms Underlying Lymphocyte Tolerance
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Self-citationTolerance and exhaustion: defining mechanisms of T cell dysfunction
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“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.”
InfluentialOh‐hora, M., Yamashita, M., Hogan, P. G., Sharma, S., Lamperti, E., Chung, W. Y., Prakriya, M., Feske, S., & Rao, A. (2008) · Nature Immunology · doi:10.1038/ni1574 · Cited by 582 · cited 2× · see citing works
“Fos and Jun are elevated only transiently after stimulation (Jain et al., 1992), whereas NFAT can remain in the nucleus for long times even in response to very low elevations of intracellular Ca2+ (Dolmetsch et al., 1997; Marangoni et al., 2013; Oh-Hora et al., 2008).”
Self-citationDoering, T. A., Crawford, A., Angelosanto, J., Paley, M., Ziegler, C. G. K., & Wherry, E. J. (2012) · Immunity · doi:10.1016/j.immuni.2012.08.021 · Cited by 542 · cited 6× · see citing works
“…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).”
InfluentialStructure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA
Chen, L., Glover, J. N. M., Hogan, P. G., Rao, A., & Harrison, S. C. (1998) · Nature · doi:10.1038/32100 · Cited by 521 · cited 7× · see citing works
“…can bind DNA as a monomer (Chen et al., 1998; Giffin et al., 2003; Jin et al., 2010; Stroud et al., 2002); it also forms cooperative complexes with FOXP3, a transcription factor central to T cell regulatory function (Bandukwala et al., 2011; Chen et al., 1998; Macián et al., 2000; Wuet al., 2006).”
InfluentialSelf-citationCalcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins
Heissmeyer, V., Macián, F., Im, S., Varma, R., Feske, S., Venuprasad, K., Gu, H., Liu, Y., Dustin, M. L., & Rao, A. (2004) · Nature Immunology · doi:10.1038/ni1047 · Cited by 515 · cited 6× · see citing works
“Thus, CA-RIT-NFAT1 expression affects two of the earliest steps of TCR signaling upstream of Ca entry; other steps in the signaling window between TCR stimulation and ER store depletion could potentially also be impaired (Heissmeyer et al., 2004).”
InfluentialSelf-citationOkamura, H., Aramburu, J. F., García‐Rodríguez, C., Viola, J. P. B., Raghavan, A., Tahiliani, M., Zhang, X., Qin, J., Hogan, P. G., & Rao, A. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00053-8 · Cited by 481 · see citing works
Self-citationMechanisms maintaining peripheral tolerance
Mueller, D. L. (2009) · Nature Immunology · doi:10.1038/ni.1817 · Cited by 461 · cited 2× · see citing works
“We propose that this negative feedback program becomes dominant in CD4 T cells under conditions of ineffective costimulation (Mueller, 2010; Nurieva et al., 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 (…”
NFATc1 Regulates PD-1 Expression upon T Cell Activation
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An Enhanced Immune Response in Mice Lacking the Transcription Factor NFAT1
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“P14+Tcra / mice were further crossed with NFAT1-deficient mice (Xanthoudakis et al., 1996) and with mice deficient in NFAT2 in the T cell lineage, obtained by breeding CD4Cre mice with mice in which exon 3 of the gene encoding NFAT2 was ‘‘floxed’’ (flanked with LoxP sites) (Figure S5A).”
InfluentialSelf-citationTerawaki, S., Chikuma, S., Shibayama, S., Hayashi, T., Yoshida, T., Okazaki, T., & Honjo, T. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003208 · Cited by 344 · cited 4× · see citing works
“The residual expression was due to NFAT4, the third NFAT protein present in immune cells: NFAT1,2-deficient cells additionally transduced with shRNA against NFAT4 (Figure 5B) produced little or no IL-2 or interferon-g (IFN-g) upon restimulation (Figure 5A) and expressed little or no LAG3 and PD-1 either under resting…”
InfluentialMacián, F., García‐Rodríguez, C., & Rao, A. (2000) · The EMBO Journal · doi:10.1093/emboj/19.17.4783 · Cited by 329 · cited 5× · see citing works
“…nuclear and therefore constitutively active (CA) (FigureS1A;Okamuraet al., 2000) andalsounable to interact with AP-1 (‘‘RIT’’ refers to three residues—R468, I469, and T535 inmouseNFAT1—that have beenmutated to interfere selectively with the NFAT:AP-1 interaction [Macián et al., 2000, 2002]).”
InfluentialSelf-citationDynamic Treg interactions with intratumoral APCs promote local CTL dysfunction
Bauer, C. A., Kim, E. Y., Marangoni, F., Carrizosa, E., Claudio, N., & Mempel, T. R. (2014) · Journal of Clinical Investigation · doi:10.1172/jci66375 · Cited by 238 · cited 7× · see citing works
“In Vivo Tumor Model Single-cell suspensions from spleens and LNs of CL4 mice were pulsed with 10 mM HA515–523 peptide for 1 hr at 37 C, then cultured with 10 ng/ml murine rIL-12 for the first 2 days and 20 ng/ml murine rIL-2 for the following 5 days as previously described (Bauer et al., 2014).”
InfluentialSelf-citationAutoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis.
Chuvpilo, S., Jankevics, E., Tyrsin, D., Akimzhanov, A., Moroz, D., Jha, M., Schulze-Luehrmann, J., Santner‐Nanan, B., Feoktistova, E., König, T., et al. (2002) · Immunity · doi:10.1016/s1074-7613(02)00329-1 · Cited by 216 · cited 2× · see citing works
“…during chronic, high-dose LCMV infection in mice after 16 hr of stimulation (they did not examine other NFAT proteins), an alternative interpretation of their data is that the short inducible isoform of NFAT2 (Chuvpilo et al., 2002) is poorly induced after restimulation of exhausted CD8+ T cells.”
CD4 + CD25 − LAG3 + regulatory T cells controlled by the transcription factor Egr-2
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“, 2007]), or upregulated in anergic CD4CD25 CD45RBLAG3 T cells compared to CD4CD25 CD45RBLAG3 T cells (bottom) (Okamura et al., 2009).”
InfluentialMolecular mechanisms of CD4+ T-cell anergy
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“mRNAs encoding E3 ligases (Fathman and Lineberry, 2007; Heissmeyer et al., 2004; Nurieva et al., 2011); phosphatases (Macián et al.”
InfluentialAnalysis of the AP-1 sites in the IL-2 promoter
Jain, J., Valge-Archer, V., & Rao, A. (1992) · The Journal of Immunology · doi:10.4049/jimmunol.148.4.1240 · Cited by 176 · cited 3× · see citing works
“Fos and Jun are elevated only transiently after stimulation (Jain et al., 1992), whereas NFAT can remain in the nucleus for long times even in response to very low elevations of intracellular Ca2+ (Dolmetsch et al., 1997; Marangoni et al., 2013; Oh-Hora et al., 2008).”
Self-citationMarangoni, F., Murooka, T. T., Manzo, T., Kim, E. Y., Carrizosa, E., Elpek, N. M., & Mempel, T. R. (2013) · Immunity · doi:10.1016/j.immuni.2012.09.012 · Cited by 164 · cited 6× · see citing works
“Fos and Jun are elevated only transiently after stimulation (Jain et al., 1992), whereas NFAT can remain in the nucleus for long times even in response to very low elevations of intracellular Ca2+ (Dolmetsch et al., 1997; Marangoni et al., 2013; Oh-Hora et al., 2008).”
InfluentialSelf-citationStructure of a Domain-Swapped FOXP3 Dimer on DNA and Its Function in Regulatory T Cells
Bandukwala, H. S., Wu, Y., Feuerer, M., Chen, Y., Barboza, B. A., Ghosh, S., Stroud, J. C., Benoist, C. O., Mathis, D. J., Rao, A., et al. (2011) · Immunity · doi:10.1016/j.immuni.2011.02.017 · Cited by 163 · cited 2× · see citing works
“…not shown), confirming predictions from the crystal structures that NFAT proteins make partially distinct contacts with Fos-Jun and FOXP proteins (Bandukwala et al., 2011; Chen et al., 1998; Wu et al., 2006), it might be possible to design reagents that disrupt the NFAT:AP-1 inter- action but…”
Self-citationA Similar DNA-binding Motif in NFAT Family Proteins and the Rel Homology Region
Jain, J., Burgeon, E., Badalian, T. M., Hogan, P. G., & Rao, A. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.8.4138 · Cited by 142 · cited 2× · see citing works
“…with IRES-GFP retrovirus, empty (mock), or expressing either CA-RIT-NFAT1 or CA-RIT-NFAT1 with four point mutations in the DNA binding loop that abolish DNA binding (DBDmut-CA-RIT-NFAT1) (Jain et al., 1995); and expanded with interleukin-2 (IL-2) to generate effector CTLs (Pipkin et al., 2010).”
Self-citationAgnellini, P., Wolint, P., Rehr, M., Cahenzli, J., Karrer, U. W., & Oxenius, A. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610335104 · Cited by 137 · cited 4× · see citing works
“Indeed, the higher basal Ca2+ concentrations observed by Agnellini et al. (2007) in exhausted CD8+ T cells and in CA-RITexpressing cells in this report would increase NFAT-dependent induction of NFAT2 under basal conditions, as also observed in ex vivo exhausted cells (Wherry et al., 2007).”
InfluentialNotch signaling regulates PD‐1 expression during CD8 + T‐cell activation
Mathieu, M., Cotta‐Grand, N., Daudelin, J., Thébault, P., & Labrecque, N. (2012) · Immunology and Cell Biology · doi:10.1038/icb.2012.53 · Cited by 131 · cited 2× · see citing works
“Other pathways might also be involved: Notch (Mathieu et al., 2013) and type I IFN (Terawaki et al., 2011) signaling regulate Pdcd1 expression, and MEK kinase (Yoon et al., 2011) and T-bet (Anderson et al., 2010) regulate TIM3 expression.”
T‐bet, a Th1 transcription factor regulates the expression of Tim‐3
Anderson, A. C., Lord, G. M., Dardalhon, V., Lee, D. H., Sabatos-Peyton, C. A., Glimcher, L. H., & Kuchroo, V. K. (2010) · European Journal of Immunology · doi:10.1002/eji.200939842 · Cited by 121 · cited 2× · see citing works
“Other pathways might also be involved: Notch (Mathieu et al., 2013) and type I IFN (Terawaki et al., 2011) signaling regulate Pdcd1 expression, and MEK kinase (Yoon et al., 2011) and T-bet (Anderson et al., 2010) regulate TIM3 expression.”
Structure of a TonEBP–DNA complex reveals DNA encircled by a transcription factor
Stroud, J. C., López‐Rodríguez, C., Rao, A., & Chen, L. (2002) · Nature Structural Biology · doi:10.1038/nsb749 · Cited by 121 · cited 2× · see citing works
“Adding to its versatility, NFAT forms dimers on palindromic kB-like sequence elements and can bind DNA as a monomer (Chen et al., 1998; Giffin et al., 2003; Jin et al., 2010; Stroud et al., 2002); it also forms cooperative complexes with FOXP3, a transcription factor central to T cell regulatory function (Bandukwala e…”
Self-citationFaroudi, M., Zaru, R., Paulet, P., Müller, S., & Valitutti, S. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.3.1128 · Cited by 111 · cited 2× · see citing works
“In contrast, signaling pathways regulating Ras, ERK, and AP-1 activation exhibit a shorter signal memory (Faroudi et al., 2003), suggesting that tolerance and/or exhaustion programs are evoked in tumor-infiltrating T cells as a result of an altered balance between NFAT NFAT1 in WT cells transduced…”
Structure of NFAT1 bound as a dimer to the HIV-1 LTR κB element
Giffin, M. J., Stroud, J. C., Bates, D. L., von Koenig, K. D., Hardin, J., & Chen, L. (2003) · Nature Structural & Molecular Biology · doi:10.1038/nsb981 · Cited by 102 · cited 2× · see citing works
“Adding to its versatility, NFAT forms dimers on palindromic kB-like sequence elements and can bind DNA as a monomer (Chen et al., 1998; Giffin et al., 2003; Jin et al., 2010; Stroud et al., 2002); it also forms cooperative complexes with FOXP3, a transcription factor central to T cell regulatory…”
Molecular mechanisms of T‐cell tolerance
Nurieva, R., Liu, X., & Dong, C. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01012.x · Cited by 88 · cited 6× · see citing works
“, 2002), hyporesponsive states induced in T cells exposed to activating signals through the T cell receptor (TCR) in the absence of positive or presence of negative costimulatory signals (Nurieva et al., 2011).”
InfluentialTranscriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance
Soto-Nieves, N., Puga, I., Abe, B. T., Bandyopadhyay, S., Baine, I., Rao, A., & Macian, F. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20082731 · Cited by 86 · cited 2× · see citing works
“…(Figure 4C) and no enrichment for kB-like sites such as the site in the Rnf128 promoter that binds NFAT1 homodimers (50- GTAACGTTTCC-30 or 50-GGATTCTTCC-30) (Soto-Nieves et al., 2009); Rnf128, which encodes the E3 ligase Grail, is upregulated in anergic CD4+ T cells (Fathman and Lineberry, 2007).”
Self-citationDiacylglycerol Kinases: Regulated Controllers of T Cell Activation, Function, and Development
Joshi, R. P., & Koretzky, G. A. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14046649 · Cited by 47 · cited 2× · see citing works
“…E3 ligases (Fathman and Lineberry, 2007; Heissmeyer et al., 2004; Nurieva et al., 2011); phosphatases (Macián et al., 2002); and other signaling proteins including caspase 3, RGS proteins, and diacylglycerol kinases (Joshi and Koretzky, 2013; Macián et al., 2002) are upregulated in both cases.”
A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo
Fehr, T. H., Lucas, C. L., Kurtz, J. M., Onoe, T., Zhao, G., Hogan, T., Vallot, C., Rao, A., & Sykes, M. (2009) · Blood · doi:10.1182/blood-2009-07-230680 · Cited by 43 · cited 2× · see citing works
“We previously linked NFAT not only to T cell activation but also to T cell ‘‘tolerance’’ and ‘‘anergy’’ (Fehr et al., 2010; Heissmeyer et al., 2004; Macián et al., 2002), hyporesponsive states induced in T cells exposed to activating signals through the T cell receptor (TCR) in the absence of…”
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“, 2007); NFAT2 was shown to be nuclear in tolerant CD8 T cells (Srinivasan and Frauwirth, 2007); and Pdcd1 expression was shown to be regulated by NFAT2 (Oestreich”
Yoon, S., Lee, M. J., Shin, D.-C., Kim, J. S., Chwae, Y., Kwon, M., Kim, K. H., & Park, S. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.05.004 · Cited by 17 · cited 2× · see citing works
“Other pathways might also be involved: Notch (Mathieu et al., 2013) and type I IFN (Terawaki et al., 2011) signaling regulate Pdcd1 expression, and MEK kinase (Yoon et al., 2011) and T-bet (Anderson et al., 2010) regulate TIM3 expression.”
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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 · see citing works
“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 · see citing works
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 · see citing works
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
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“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 · see citing works
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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 · see citing works
CTLA-4: a moving target in immunotherapy
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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 1,178 · see citing works
“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 · see citing works
CD8+ T cell differentiation and dysfunction in cancer
Philip, M., & Schietinger, A. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00574-3 · Cited by 1,052 · see citing works
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Clinical implications of T cell exhaustion for cancer immunotherapy
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The epigenetic landscape of T cell exhaustion
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 · see citing works
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Chromatin states define tumour-specific T cell dysfunction and reprogramming
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c-Jun overexpression in CAR T cells induces exhaustion resistance
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 · see citing works
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TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection
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 900 · see citing works
NR4A transcription factors limit CAR T cell function in solid tumours
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 · see citing works
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“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 · see citing works
“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
Chen, Z., Ji, Z., Ngiow, S. F., Manne, S., Cai, Z., Huang, A. C., Johnson, J., Staupe, R. P., Bengsch, B., Xu, C., et al. (2019) · Immunity · doi:10.1016/j.immuni.2019.09.013 · Cited by 709 · see citing works
Cold and hot tumors: from molecular mechanisms to targeted therapy
Wu, B., Zhang, B., Li, B., Wu, H., & Jiang, M. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01979-x · Cited by 751 · see citing works
Targeting the epigenetic regulation of antitumour immunity
Hogg, S. J., Beavis, P. A., Dawson, M. A., & Johnstone, R. W. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0077-5 · Cited by 653 · see citing works
Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
Weber, E. W., Parker, K. R., Sotillo, E., Lynn, R. C., Anbunathan, H., Lattin, J., Good, Z., Belk, J. A., Dániel, B., Klysz, D. D., et al. (2021) · Science · doi:10.1126/science.aba1786 · Cited by 629 · see citing works
Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends
Sun, Q., Hong, Z., Zhang, C., Wang, L., Han, Z., & Ma, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01522-4 · Cited by 598 · see citing works
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Multidimensional communication in the microenvirons of glioblastoma
Broekman, M. L. D., Maas, S. L. N., Abels, E. R., Mempel, T. R., Krichevsky, A. M., & Breakefield, X. O. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0025-8 · Cited by 574 · see citing works
Self-citationSingle-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection
Yao, C., Sun, H.-W., Lacey, N. E., Ji, Y., Moseman, E. A., Shih, H.-Y., Heuston, E. F., Kirby, M., Anderson, S., Cheng, J., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0403-4 · Cited by 549 · see citing works
Regulatory circuits of T cell function in cancer
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Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction
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 · see citing works
Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate
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 544 · see citing works
Myeloid immunosuppression and immune checkpoints in the tumor microenvironment
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CD8+ T Cell Exhaustion in Cancer
Dolina, J. S., Budimir, N., Thomas, G. D., & Salek‐Ardakani, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.715234 · Cited by 487 · see citing works
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 464 · see citing works
“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?
Kallies, A., Zehn, D., & Utzschneider, D. T. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0223-7 · Cited by 462 · see citing works
LAG-3: from molecular functions to clinical applications
Maruhashi, T., Sugiura, D., Okazaki, I., & Okazaki, T. (2020) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-001014 · Cited by 462 · see citing works
Siglecs as Immune Cell Checkpoints in Disease
Duan, S., & Paulson, J. C. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-102419-035900 · Cited by 452 · see citing works
“In mice, naive T cells also express no Siglecs, but transcription of Siglec-F is highly elevated in both CD8+ and CD4+ T cells in a mouse model of T cell exhaustion (195), and Siglec-E is upregulated on tumor-infiltrating T cells in mouse tumor models (196).”
BackgroundT‐cell exhaustion in HIV infection
Fenwick, C. W., Joo, V., Jacquier, P., Noto, A., Banga, R., Perreau, M., & Pantaleo, G. (2019) · Immunological Reviews · doi:10.1111/imr.12823 · Cited by 412 · see citing works
T Cell Dysfunction and Exhaustion in Cancer
Zhang, Z., Liu, S., Zhang, B., Qiao, L., Zhang, Y., & Zhang, Y. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00017 · Cited by 385 · see citing works
Self-citationPD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy?
Simon, S., & Labarrière, N. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1364828 · Cited by 399 · see citing works
“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 388 · see citing works
Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment
Zhao, Y., Shao, Q., & Peng, G. (2020) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0344-8 · Cited by 382 · see citing works
IL-2 regulates tumor-reactive CD8+ T cell exhaustion by activating the aryl hydrocarbon receptor
Liu, Y., Zhou, N., Zhou, L., Wang, J., Zhou, Y., Zhang, T., Fang, Y., Deng, J., Gao, Y., Liang, X., et al. (2021) · Nature Immunology · doi:10.1038/s41590-020-00850-9 · Cited by 372 · see citing works
Stromal biology and therapy in pancreatic cancer: ready for clinical translation?
Neeße, A., Bauer, C. A., Öhlund, D., Lauth, M., Buchholz, M., Michl, P., Tuveson, D. A., & Gress, T. M. (2018) · Gut · doi:10.1136/gutjnl-2018-316451 · Cited by 348 · see citing works
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BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells
Seo, H., González‐Avalos, E., Zhang, W., Ramchandani, P., Yang, C., Lio, C. J., Rao, A., & Hogan, P. G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00964-8 · Cited by 353 · see citing works
Self-citationT Cell Dysfunction in Cancer Immunity and Immunotherapy
Xia, A., Zhang, Y., Jiang, X., Yin, T., & Lu, X. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01719 · Cited by 338 · see citing works
Self-citationWu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42634-3 · Cited by 334 · see citing works
“Chroni-cally stimulated T cells express predominantly the short isoform of NFATc1 36,16,37 .”
Epigenetic regulation of T cell exhaustion
Belk, J. A., Dániel, B., & Satpathy, A. T. (2022) · Nature Immunology · doi:10.1038/s41590-022-01224-z · Cited by 334 · see citing works
Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer
Granier, C., Guillebon, É. D., Blanc, C., Roussel, H., Badoual, C., Colin, E., Saldmann, A., Gey, A., Oudard, S. M., & Tartour, É. (2017) · ESMO Open · doi:10.1136/esmoopen-2017-000213 · Cited by 323 · see citing works
T-cell Dysfunction in Glioblastoma: Applying a New Framework
Woroniecka, K. I., Rhodin, K. E., Chongsathidkiet, P., Keith, K. A., & Fecci, P. E. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-0047 · Cited by 316 · see citing works
“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
Utzschneider, D. T., Gabriel, S. S., Chisanga, D., Gloury, R., Gubser, P. M., Vasanthakumar, A., Shi, W., & Kallies, A. (2020) · Nature Immunology · doi:10.1038/s41590-020-0760-z · Cited by 306 · see citing works
Exhaustion-associated regulatory regions in CD8 + tumor-infiltrating T cells
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 312 · see citing works
“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
Scott-Browne, J. P., López-Moyado, I. F., Trifari, S., Wong, V., Chávez, L., Rao, A., & Pereira, R. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.10.028 · Cited by 309 · see citing works
Self-citationAP-1 Transcription Factors as Regulators of Immune Responses in Cancer
Atsaves, V., Leventaki, V., Rassidakis, G. Z., & Claret, F. X. (2019) · Cancers · doi:10.3390/cancers11071037 · Cited by 280 · see citing works
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“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
Vaeth, M., Maus, M., Klein‐Hessling, S., Freinkman, E., Yang, J. J. J., Eckstein, M., Cameron, S. B., Turvey, S. E., Serfling, E., Berberich‐Siebelt, F., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.09.003 · Cited by 271 · see citing works
“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 274 · see citing works
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“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].”
BackgroundKim, 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 · see citing works
Challenges 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 271 · see citing works
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 256 · see citing works
“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 256 · see citing works
Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans
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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 243 · see citing works
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 242 · see citing works
RASA2 ablation in T cells boosts antigen sensitivity and long-term function
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Memory T cell, exhaustion, and tumor immunity
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“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 226 · see citing works
Divergent clonal differentiation trajectories of T cell exhaustion
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T cell Allorecognition Pathways in Solid Organ Transplantation
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“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 216 · see citing works
“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 209 · see citing works
In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer
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“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 213 · see citing works
Expansion of tumor-associated Treg cells upon disruption of a CTLA-4-dependent feedback loop
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Self-citationNFATc1 controls the cytotoxicity of CD8+ T cells
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Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker
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Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development
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Activation or exhaustion of CD8+ T cells in patients with COVID-19
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NFAT control of immune function: New Frontiers for an Abiding Trooper
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“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 186 · see citing works
“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 190 · see citing works
Calcium–NFAT transcriptional signalling in T cell activation and T cell exhaustion
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“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
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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 · see citing works
“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
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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 174 · see citing works
- 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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