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The mTOR Kinase Determines Effector versus Memory CD8+ T Cell Fate by Regulating the Expression of Transcription Factors T-bet and Eomesodermin
Open accessAbstract
The mechanisms underpinning integration of instructions that program naive CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that interleukin-12 (IL-12) enhanced and sustained antigen and costimulatory molecule (B7.1)-induced mTOR kinase activity in naive CD8+ (OT-I) T cells via phosphoinositide 3-kinase and STAT4 transcription factor pathways. Blocking mTOR activity by rapamycin reversed IL-12-induced effector functions because of loss of persistent expression of the transcription factor T-bet. Rapamycin treatment of IL-12-conditioned OT-I cells promoted persistent Eomesodermin expression and produced memory cell precursors that demonstrated enhanced sustenance and antigen-recall responses upon adoptive transfer. The memory cell precursors showed greater tumor efficacy than IL-12-conditioned effector OT-I cells. These results identify mTOR as the central regulator of transcriptional programs that determine effector and/or memory cell fates in CD8+ T cells. Targeting mTOR activity offers new opportunities to regulate CD8+ T cell-mediated immunity.
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“Consistent with this, the drug rapamycin, which also inhibits mTORC1, enhances the generation of CD8 TM cells (17, 19, 20).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [19]
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Cites
TOR signaling in growth and metabolism
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BackgroundInfluentialUpstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181 · cited 2×
“Although the kinase mTOR has been implicated as an integrator of various extracellular signals and a sensor for internal energy levels for determination of cell fate (Hay and Sonenberg, 2004), the role for mTOR in integrating instructions that program naive CD8 T cells for type I effector differentiation is unclear.”
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Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000) · Cell · doi:10.1016/s0092-8674(00)80702-3 · Cited by 3,589 · cited 1×
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Morgan, R. A., Dudley, M. E., Wunderlich, J. R., Hughes, M. S., Yang, J. C., Sherry, R. M., Royal, R. E., Topalian, S. L., Kammula, U. S., Restifo, N. P., et al. (2006) · Science · doi:10.1126/science.1129003 · Cited by 2,603 · cited 2×
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BackgroundTOR, a Central Controller of Cell Growth
Schmelzle, T., & Hall, M. N. (2000) · Cell · doi:10.1016/s0092-8674(00)00117-3 · Cited by 1,914 · cited 2×
“In agreement, with the reported role for mTOR in regulating cell size (Schmelzle and Hall, 2000) and the expression of L-type amino acid transporter (CD98) (Cornish et al.”
BackgroundLineage relationship and protective immunity of memory CD8 T cell subsets
Wherry, E. J., Teichgräber, V., Becker, T. C., Masopust, D., Kaech, S. M., Antia, R., von Andrian, U. H., & Ahmed, R. (2003) · Nature Immunology · doi:10.1038/ni889 · Cited by 1,864 · cited 2×
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BackgroundInfluentialInterleukin-7 mediates the homeostasis of naïve and memory CD8 T cells in vivo
Schluns, K. S., Kieper, W. C., Jameson, S. C., & Lefrançois, L. (2000) · Nature Immunology · doi:10.1038/80868 · Cited by 1,619 · cited 2×
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BackgroundmTOR regulates memory CD8 T-cell differentiation
Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., Larsen, C. P., & Ahmed, R. (2009) · Nature · doi:10.1038/nature08155 · Cited by 1,575
Enhancing CD8 T-cell memory by modulating fatty acid metabolism
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“…reports have demonstrated the role of mTOR in regulating CD8+ T cell trafficking (Sinclair et al., 2008) and memory differentiation (Araki et al., 2009; Pearce et al., 2009), but the molecular mechanisms by which mTOR regulates CD8+ T cell differentiation or trafficking remain uncharacterized.”
BackgroundInfluential
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Sorted by citations
Items 201–300 of 655
Waickman, A. T., & Powell, J. D. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1103143 · Cited by 64
“Rao and colleagues (45) were able to demonstrate that treating CD8 T cells with rapamycin promoted memory generation in part by inhibiting T-bet expression and facilitating the expression of eomesodermin.”
BackgroundTumor suppressor TSC1 is critical for T-cell anergy
Xie, D., Wu, J., Lou, Y., & Zhong, X. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119744109 · Cited by 62
“Contrary to its positive role in promoting T-cell activation and effector T-cell function during primary immune responses, mTOR inhibits memory CD8 T-cell formation and function during viral infection (17, 18).”
CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer
Tedeschi, V., Paldino, G., Kunkl, M., Paroli, M., Sorrentino, R., Tuosto, L., & Fiorillo, M. T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063374 · Cited by 65
“In turn, the expression of T-bet and Eomes is controlled by mTOR, a key regulator of cellular metabolism that is crucial for the development of CD8+ T cells [24].”
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Wu, Y., Wu, Y., Gao, Z., Yu, W., Zhang, L., & Zhou, F. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02327-3 · Cited by 78
iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions
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“Our findings that mTORC1 negatively controls T-bet expression and that TSC1 promotes T-bet expression via inhibiting mTORC1 in iNKT cells are surprising, as T-bet expression has been reported to be dependent on mTORC1 activity in both CD4 and CD8 T cells (28, 30).”
BackgroundPost-transplantation malignancies: here today, gone tomorrow?
Geissler, E. K. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.186 · Cited by 63
NFκB–Pim-1–Eomesodermin axis is critical for maintaining CD8 T-cell memory quality
Knudson, K. M., Pritzl, C. J., Saxena, V., Altman, A., Daniëls, M. A., & Teixeiro, E. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1608448114 · Cited by 62
“Upon infection, high levels of inflammation repress Eomes and increase T-bet expression in a process that is dependent on the mechanistic target of rapamycin (mTOR) signaling pathway (10).”
BackgroundInfluentialIL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection
Renkema, K. R., Lee, J., Lee, Y. J., Hamilton, S. E., Hogquist, K. A., & Jameson, S. C. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20151359 · Cited by 61
“…whereas Eomes expression levels peak in memory CD8+ T cells, and Eomes is required for efficient production of central memory CD8+ T cells (Joshi et al., 2007; Banerjee et al., 2010; Rao et al., 2010), as well as innate memory CD8+ T cells (Weinreich et al., 2009; Sosinowski et al., 2013).”
BackgroundRegulation of Lipid Signaling by Diacylglycerol Kinases during T Cell Development and Function
Krishna, S., & Zhong, X. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00178 · Cited by 58
“Other studies have revealed that the temporal kinetics of mTORc1 activity may play a critical role in effector versus memory differentiation of CD8 cells (152, 153).”
BackgroundUnique Features of Naive CD8+ T Cell Activation by IL-2
Cho, J.-H., Kim, H.-O., Kim, K., Yang, D., Surh, C. D., & Sprent, J. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1302293 · Cited by 59
“It is of interest that the lack of a contraction phase seen in vivo after IL-2 stimulation has also been reported for CD8 cells stimulated with Ag plus rapamycin (71), the latter being known to repress T-bet expression while enhancing Eomes expression.”
BackgroundGeissler, E. K., & Schlitt, H. J. (2010) · Kidney International · doi:10.1038/ki.2010.324 · Cited by 59
mTOR and metabolic regulation of conventional and regulatory T cells
Liu, C., Chapman, N. M., Karmaus, P. W. F., Zeng, H., & Chi, H. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.2ri0814-408r · Cited by 59
“This phenotype is linked to the IL-12-driven expression of the transcription factor, Eomesodermin [34], which favors memory CD8+ T cell differentiation [33].”
BackgroundIL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues
Sowell, R., Goldufsky, J. W., Rogozinska, M., Quiles, Z., Cao, Y., Castillo, E. F., Finnegan, A., & Marzo, A. L. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1501638 · Cited by 60
“This possibility is supported by: 1) our observations that mTOR deficiency leads to sequestration of effectors in SLOs, 2) previous reports that T-bet and Blimp-1 can promote trafficking of effectors in the spleen and their exit into the circulation, and 3) reports that subsequent repression of T-bet is required for t…”
BackgroundInfluentialThe Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma
Reuss, A. M., Groos, D., Buchfelder, M., & Savaskan, N. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115518 · Cited by 58
New drug targets in metastatic melanoma
Homet, B., & Ribas, A. (2013) · The Journal of Pathology · doi:10.1002/path.4259 · Cited by 58
“Inhibiting mTOR signalling has been shown to have immune-stimulating effects beyond targeting the mTOR oncogene, resulting in the generation of long-lived memory CD8+ T cells [82,83] and could be another partner for combinatorial therapy with immunotherapy.”
Therapeutic potential of STAT4 in autoimmunity
Liang, Y., Pan, H., & Ye, D. (2014) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2014.920325 · Cited by 57
“[87] assessed the role of STAT4 in IL-12-mediated mammalian target of rapamycin (mTOR) activity (which determines CD8T cells effector and memory functional response) in CD8T cells.”
BackgroundmTOR signaling in immune cells and its implications for cancer immunotherapy
Zeng, H. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.08.038 · Cited by 54
Zhang, L., Zhang, H., Li, L., Xiao, Y., Rao, E., Miao, Z., Chen, H., Sun, L., Li, H., Liu, G., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030592 · Cited by 54
Metabolic regulation of T cell differentiation and function
Park, B. V., & Pan, F. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.07.027 · Cited by 58
Transcription factor regulation of CD8+ T‐cell memory and exhaustion
Angelosanto, J., & Wherry, E. J. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00927.x · Cited by 56
Rapalogs Efficacy Relies on the Modulation of Antitumor T-cell Immunity
Beziaud, L., Mansi, L., Ravel, P., Joseph, E. L. M., Laheurte, C., Rangan, L., Bonnefoy, F., Pallandre, J., Boullerot, L., Gamonet, C., et al. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2452 · Cited by 60
Dufour, M., Dormond-Meuwly, A., Demartines, N., & Dormond, O. (2011) · Cancers · doi:10.3390/cancers3022478 · Cited by 55
“memory T cell response after pathogen infection [78,79] and also promotes CD8 + T cell-mediated antitumor activity [80].”
BackgroundMineharu, Y., Kamran, N., Lowenstein, P. R., & Castro, M. G. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0400 · Cited by 53
“Rapamycin, through its effect on the mTOR signaling cascade, has also been shown to promote cytotoxic CD8þ T-cell responses and induce immunologic memory in a T-cell intrinsic manner (19, 27, 28).”
BackgroundIto, D., Nojima, S., Nishide, M., Okuno, T., Takamatsu, H., Kang, S., Kimura, T., Yoshida, Y., Morimoto, K., Maeda, Y., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1403038 · Cited by 53
“In contrast, only a few studies have suggested the involvement of mTORC1 signaling in CD8 T cell responses (9).”
BackgroundArneja, A., Johnson, H., Gabrovsek, L., Lauffenburger, D. A., & White, F. M. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1302291 · Cited by 53
“Our results showing a linear relationship between cell size and mTOR pathway activation for both IL-2– and IL-15–stimulated F15R-Kit cells lend support to this idea (36, 38, 39).”
BackgroundResultFatty acid metabolism in adaptive immunity
Zhou, X., Zhu, X., & Zeng, H. (2021) · FEBS Journal · doi:10.1111/febs.16296 · Cited by 58
Cash, H. A., Shah, S., Moore, E. C., Caruso, A. M., Uppaluri, R., Waes, C. V., & Allen, C. T. (2015) · Oncotarget · doi:10.18632/oncotarget.5063 · Cited by 52
“com/oncotarget of memory T-cell populations, perhaps at the expense of effector populations, and induces development of FoxP3+ Tregs [33–35].”
BackgroundTaylor, J. J., & Jenkins, M. K. (2011) · Current Opinion in Immunology · doi:10.1016/j.coi.2011.03.010 · Cited by 52
Mammalian target of rapamycin and tuberous sclerosis complex
Wataya‐Kaneda, M. (2015) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2015.04.005 · Cited by 54
“Several investigators have implicated mTOR in the regulation of the effector-to-memory ratio and the transition between both states [37] (Fig.”
BackgroundDynamic Metabolic State of Tissue Resident CD8 T Cells
Konjar, Š., & Veldhoen, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01683 · Cited by 50
Non-immunogenic, low-toxicity and effective glioma targeting MTI-31 liposomes
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A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS
Maccari, M. E., Fuchs, S. P., Küry, P., Andrieux, G., Völkl, S., Bengsch, B., Lorenz, M. R., Heeg, M., Rohr, J., Jägle, S., et al. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20192191 · Cited by 51
“The absence of T-BET in FC T cells was unexpected because T-BET upregulation has been linked to T cell activation and mTOR signaling (Intlekofer et al., 2005; Joshi et al., 2007; Rao et al., 2010).”
BackgroundRapamycin-Induced Enhancement of Vaccine Efficacy in Mice
Jagannath, C., & Bakhru, P. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-430-8_18 · Cited by 50
“Although enhanced processing of antigens in DCs is a major mechanism of rapamycin, recent studies have found that rapamycin affects mTOR signaling within T cells (4, 12, 13).”
BackgroundKang, S., & Tang, H. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.572677 · Cited by 57
“After the immune response subsides, the effector T cell population contracts and differentiates into long-lived memory cells with key metabolic pathway associated with effector function downregulated, such as glycolysis and mTOR activity (23).”
BackgroundDynamics of TCR repertoire and T cell function in COVID-19 convalescent individuals
Luo, L., Liang, W., Pang, J., Xu, G., Chen, Y., Guo, X., Wang, X., Zhao, Y., Lai, Y., Liu, Y., et al. (2021) · Cell Discovery · doi:10.1038/s41421-021-00321-x · Cited by 47
Jung, J., Overgaard, N. H., Burke, M., Isbel, N. M., Frazer, I. H., Simpson, F., & Wells, J. W. (2015) · International Journal of Cancer · doi:10.1002/ijc.29450 · Cited by 53
“In contrast, rapamycin-induced inhibition of the mTOR pathway in CD8(1) T-cells promotes the differentiation of highly functional memory CD8(1) T-cells with enhanced sustenance and antigen-recall responsiveness.(37,38) This preferential differentiation of T-cells and possibly other immune cell sub-populations, may pot…”
BackgroundCordero, E., Pérez-Ordóñez, A., Aydillo, T., Torre‐Cisneros, J., Gavaldà, J., Lara, R., Segura, C., Len, Ó., Cabral, E., Gasch, A., et al. (2011) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03692.x · Cited by 50
“In this context, m-TOR may be acting as an integrator of signals on metabolic demand regulating the further effect on memory differentiation (13,16).”
BackgroundPollizzi, K. N., Waickman, A. T., Patel, C. H., Sun, I., & Powell, J. D. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121710 · Cited by 51
Enhancing adoptive cancer immunotherapy with Vγ2Vδ2 T cells through pulse zoledronate stimulation
Nada, M. H., Wang, H., Workalemahu, G., Tanaka, Y., & Morita, C. T. (2017) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0209-6 · Cited by 52
“The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin.”
BackgroundImmunosuppressive enzymes in the tumor microenvironment
Molinier‐Frenkel, V., & Castellano, F. (2017) · FEBS Letters · doi:10.1002/1873-3468.12784 · Cited by 53
Maeda, N., Maruhashi, T., Sugiura, D., Shimizu, K., Okazaki, I., & Okazaki, T. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.010379 · Cited by 49
“1, A and B), consistent with a previous report that mTOR induces T-box transcription factor (T-bet), which represses transcription of PD-1 mRNA (18, 19).”
BackgroundResultTranscriptional regulation of adaptive and innate lymphoid lineage specification
Spinner, C. A., & Lazarevic, V. (2020) · Immunological Reviews · doi:10.1111/imr.12935 · Cited by 54
Fernández-García, J., Franco, F., Parik, S., Altea‐Manzano, P., Pane, A. A., Broekaert, D., Elsen, J. V., Conza, G. D., Vermeire, I., Schalley, T., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111639 · Cited by 53
Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity
Kavazović, I., Han, H., Balzaretti, G., Slinger, E., Lemmermann, N. A. W., ten Brinke, A., Merkler, D., Köster, J., Bryceson, Y. T., de Vries, N., et al. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000648 · Cited by 49
Combining mTOR Inhibitors and T Cell-Based Immunotherapies in Cancer Treatment
Hage, A., & Dormond, O. (2021) · Cancers · doi:10.3390/cancers13061359 · Cited by 51
“Immunostimulatory activity of rapamycin was first demonstrated in infection and later in cancer models, where rapamycin stimulated the generation of memory CD8+ T cells [86,87].”
BackgroundGlycolysis in tumor microenvironment as a target to improve cancer immunotherapy
Xiao, C., Tian, H., Zheng, Y., Yang, Z., Li, S., Fan, T. T., Xu, J., Bai, G., Liu, J., Deng, Z., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1013885 · Cited by 50
“, 2009), especially the newly differentiated memory CD8T cells equipped with more superior anti-tumor activity than IL-2-inducing effector T cells (Rao et al., 2010).”
BackgroundmTOR Regulation of Lymphoid Cells in Immunity to Pathogens
Keating, R., & McGargill, M. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00180 · Cited by 50
“In vitro inhibition of mTOR with a low dose of rapamycin reduced T-bet expression and enhanced Eomes expression in CD8+ T cells, leading to augmented memory responses following adoptive transfer in vivo (74).”
BackgroundNFκB signaling in T cell memory
Daniels, M. A., Luera, D., & Teixeiro, E. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1129191 · Cited by 47
“Yet, TCR-dependent NFkB signaling deficient CD8 T cells, are deficient in Eomes but not in T-bet or Blimp1 expression.”
BackgroundInfluentialDiacylglycerol 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 48
Modulation of mTORC1 Signaling Pathway by HIV-1
Akbay, B., Shmakova, A., Vassetzky, Y. S., & Dokudovskaya, S. (2020) · Cells · doi:10.3390/cells9051090 · Cited by 49
The New Era of Cancer Immunotherapy
Khalil, D. N., Budhu, S., Gasmi, B., Zappasodi, R., Hirschhorn-Cymerman, D., Plitt, T., Henau, O. D., Zamarin, D., Holmgaard, R., Murphy, J. T., et al. (2015) · Advances in cancer research · doi:10.1016/bs.acr.2015.04.010 · Cited by 46
Targeting TOR dependence in cancer
Janes, M. R., & Fruman, D. A. (2010) · Oncotarget · doi:10.18632/oncotarget.110 · Cited by 46
“Paradoxically, rapamycin enhances the generation and quality of CD8 T cell memory [52, 53], and also potentiates inflammatory responses of innate immune cells [49-51].”
BackgroundHaug, T., Aigner, M., Peuser, M., Strobl, C. D., Hildner, K. M., Mougiakakos, D., Bruns, H., Mackensen, A., & Völkl, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00883 · Cited by 46
“Notably, mTOR signaling and metabolic reprogramming are involved in the differentiation of memory and effector T-cells by regulation of the transcription factors T-bet and Eomes (38).”
BackgroundInfluentialPedicord, V. A., Cross, J. R., Montalvo-Ortiz, W., Miller, M. L., & Allison, J. P. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1402390 · Cited by 45
“Metabolic changes regulated by the mTOR pathway have recently been described to be important for memory CD8 T cell differentiation and function (8, 12, 25), and our data corroborate a role for fatty acid metabolism in the combination anti–CTLA-4/rapamycin–mediated enhancement of memory CD8 T cell formation and functio…”
BackgroundSpecific Gut Commensal Flora Locally Alters T Cell Tuning to Endogenous Ligands
Chappert, P., Bouladoux, N. J., Naik, S., & Schwartz, R. H. (2013) · Immunity · doi:10.1016/j.immuni.2013.06.005 · Cited by 44
“In CD8 T cells, IL-12p70 can sustain mTOR activation (Rao et al., 2010), a key step in preventing the induction of clonal anergy in vitro (Allen et al., 2004; Zheng et al., 2007).”
mTOR Inhibition Improves Antitumor Effects of Vaccination with Antigen-Encoding RNA
Diken, M., Kreiter, S., Vascotto, F., Selmi, A., Attig, S., Diekmann, J., Huber, C., Türeci, Ö., & Sahin, U. (2013) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-13-0046 · Cited by 45
Modulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity
Yang, H., Wang, X., Zhang, Y., Liu, H., Liao, J., Shao, K., Chu, Y., & Liu, G. (2013) · Journal of Cellular Physiology · doi:10.1002/jcp.24426 · Cited by 45
“The presence of rapamycin reverses IL-12induced effector functions due to the decreased transcription factor T-bet and increased eomesodermin expression, resulting in the generation of memory T cells (Rao et al., 2010).”
BackgroundmTOR signaling and transcriptional regulation in T lymphocytes
Zeng, H., & Chi, H. (2014) · Transcription · doi:10.4161/trns.28263 · Cited by 45
“Importantly, inhibition of mTORC1 reduces IL-12-induced expression of T-bet, a transcription factor essential for effector differentiation, and activates Eomesodermin (Eomes), a transcription factor that enhances memory cell formation.(59,60) Thus, mTOR dictates effector and memory differentiation in part through diff…”
BackgroundMicroRNAs and Their Targets Are Differentially Regulated in Adult and Neonatal Mouse CD8+ T Cells
Wissink, E. M., Smith, N. L., Spektor, R., Rudd, B. D., & Grimson, A. (2015) · Genetics · doi:10.1534/genetics.115.179176 · Cited by 45
“Expression of Tbx21 and Eomes is low in adult naive cells, and their upregulation during infection is driven by external cell signaling (Takemoto et al. 2006; Joshi et al. 2007; Cruz-Guilloty et al. 2009; Pipkin et al. 2010; Rao et al. 2010, 2012; Kaech and Cui 2012).”
BackgroundSugar or Fat?—Metabolic Requirements for Immunity to Viral Infections
Shehata, H. M., Murphy, A. J., Lee, M. K. S., Gardiner, C. M., Crowe, S. M., Sanjabi, S., Finlay, D. K., & Palmer, C. S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01311 · Cited by 47
mTOR Inhibition Role in Cellular Mechanisms
Zaza, G., Granata, S., Caletti, C., Signorini, L. F., Stallone, G., & Lupo, A. (2018) · Transplantation · doi:10.1097/tp.0000000000001806 · Cited by 46
Jung, J., Veitch, M., Bridge, J. A., Overgaard, N. H., Cruz, J. L. G., Linedale, R., Franklin, M. E., Saunders, N. A., Simpson, F., Frazer, I. H., et al. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1479627 · Cited by 43
Regulation of T cell immunity by cellular metabolism
Hu, Z., Zou, Q., & Su, B. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0668-2 · Cited by 43
Zhou, A. C., Batista, N. V., & Watts, T. H. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1800795 · Cited by 44
Early Decision: Effector and Effector Memory T Cell Differentiation in Chronic Infection
Opata, M. M., & Stephens, R. (2014) · Current Immunology Reviews · doi:10.2174/1573395509666131126231209 · Cited by 46
More TOR: The expanding role of mTOR in regulating immune responses
Patel, C. H., & Powell, J. D. (2025) · Immunity · doi:10.1016/j.immuni.2025.06.010 · Cited by 48
Differential Regulation of Primary and Memory CD8 T Cell Immune Responses by Diacylglycerol Kinases
Shin, J., O’Brien, T. F., Grayson, J. M., & Zhong, X. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102265 · Cited by 46
Arnold, C. R., Pritz, T., Brunner, S., Knabb, C., Salvenmoser, W., Holzwarth, B., Thedieck, K., & Grubeck-Loebenstein, B. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.018 · Cited by 42
Su, Y., Sun, X., Liu, X., Qu, Q., Yang, L., Chen, Q., Liu, F., Li, Y., Wang, Q., Huang, B., et al. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01315-2 · Cited by 42
“noted that RAPA has been reported to mitigate GVHD by supporting regulatory T cell expansion [57, 58] and function while inhibiting CD4+ helper cells [59], effector CD8+ T cells [60] and dendritic cells [61].”
BackgroundmiR-150-Mediated Foxo1 Regulation Programs CD8+ T Cell Differentiation
Ban, Y. H., Oh, S., Seo, S. H., Kim, S., Choi, I.-P., Greenberg, P. D., Chang, J., Kim, T., & Ha, S. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.065 · Cited by 42
Stoycheva, D., Deiser, K., Stärck, L., Nishanth, G., Schlüter, D., Uckert, W., & Schüler, T. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1402058 · Cited by 40
“Reduced mTOR signaling facilitates the formation of IFN-gR TMPs Signaling via mTOR limits CD8 TMP/TM differentiation (18, 19).”
BackgroundInfluentialChi-Sabins, N., Chornoguz, O., Leander, K. R., Kaplan, F. M., Carter, R., Kinder, M., Bachman, K. E., Verona, R. I., Shen, S., Bhargava, V., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1701030 · Cited by 41
Common gamma chain cytokines and CD8 T cells in cancer
Shourian, M., Beltra, J., Bourdin, B., & Decaluwe, H. (2019) · Seminars in Immunology · doi:10.1016/j.smim.2019.101307 · Cited by 43
When Cells Suffocate: Autophagy in Cancer and Immune Cells under Low Oxygen
Schlie, K., Spowart, J. E., Hughson, L. R. K., Townsend, K. N., & Lum, J. J. (2011) · International Journal of Cell Biology · doi:10.1155/2011/470597 · Cited by 45
“This effect was determined to be mediated by the ability of mTOR to influence the transcription factors t-bet and eomesodermin, which were shown to be crucial in determining effector T cell fate [94].”
BackgroundMetabolic dynamics instruct CD8 + T‐cell differentiation and functions
Bevilacqua, A., Li, Z., & Ho, P. (2022) · European Journal of Immunology · doi:10.1002/eji.202149486 · Cited by 41
Foxp3+ T Cells Inhibit Antitumor Immune Memory Modulated by mTOR Inhibition
Wang, Y., Sparwasser, T. D., Figlin, R. A., & Kim, H. L. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2928 · Cited by 40
Chen, H., Zhang, L., Zhang, H., Xiao, Y., Shao, L., Li, H., Yin, H., Wang, R., Liu, G., Corley, D. A., et al. (2013) · The FASEB Journal · doi:10.1096/fj.13-235408 · Cited by 40
Kurtuluş, S., Tripathi, P., & Hildeman, D. A. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00404 · Cited by 40
Uhrf1 Controls iNKT Cell Survival and Differentiation through the Akt-mTOR Axis
Cui, Y., Chen, X., Zhang, J., Sun, X., Liu, H., Bai, L., Xu, C., & Liu, X. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.03.016 · Cited by 40
“Besides, Akt-mTOR axis has been reported to modulate the expression of critical transcription factors for T cell differentiation such as T-bet and Foxp3 (Haxhinasto et al., 2008; Rao et al., 2010).”
BackgroundSwadling, L., Halliday, J., Kelly, C., Brown, A., Capone, S., Ansari, M. A., Bonsall, D., Richardson, R., Hartnell, F., Collier, J. R., et al. (2016) · Vaccines · doi:10.3390/vaccines4030027 · Cited by 40
“The transcription factor Tbet controls a programme of gene expression that confers cytolytic potential and production of antiviral cytokines (in particular IFNγ) in CD8+ T-cells [56,57].”
BackgroundOlesin, E., Nayar, R., Lakshmi, P. S., & Berg, L. J. (2018) · ImmunoHorizons · doi:10.4049/immunohorizons.1800046 · Cited by 40
“Eomesodermin (Eomes) (17, 19, 27), Tcf1 (28, 29), Id3 (24, 30),”
Diverse Roles of Akt in T cells
Abdullah, L., Hills, L. B., Winter, E. B., & Huang, Y. H. (2021) · Immunometabolism · doi:10.20900/immunometab20210007 · Cited by 42
“mTOR kinase increases the T-bet to Eomes ratio and in turn promotes the effector over memory cell fate in activated CD8 T cells [45].”
BackgroundRingquist, R., Ghoshal, D., Jain, R., & Roy, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114003 · Cited by 39
Caza, T. N., Wijewardena, C., Al-Rabadi, L. F., & Perl, A. (2022) · Translational research · doi:10.1016/j.trsl.2022.03.004 · Cited by 40
B cell adaptor for PI3-kinase (BCAP) modulates CD8+ effector and memory T cell differentiation
Singh, M. D., Ni, M., Sullivan, J. M., Hamerman, J. A., & Campbell, D. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20171820 · Cited by 38
“Consistent with the notion that strong PI3K signaling favors differentiation of TECs (Rao et al., 2010), at day 7 after infection we observed a significant reduction in the frequency of KLRG1+CD127− cells among BCAP-deficient OT-I cells compared with WT OT-I cells in both spleen and lungs (Fig.”
ResultInfluentialNazari, N., Jafari, F., Ghalamfarsa, G., Hadinia, A., Atapour, A., Ahmadi, M., Dolati, S., & Rostamzadeh, D. (2021) · Immunology and Cell Biology · doi:10.1111/imcb.12477 · Cited by 40
“expression.(6,39,40) Therefore, understanding the expression profile of miRNAs during CD8 T-cell activation and differentiation may explain their critical role in the”
BackgroundWei, Y., Ding, J., Li, J., Cai, S., Liu, S., Hong, L., Yin, T., Zhang, Y., & Diao, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.717014 · Cited by 40
Dailah, H. G., Hommdi, A. A., Koriri, M. D., Algathlan, E. M., & Mohan, S. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e24559 · Cited by 42
Rubinstein, M. P., Cloud, C. A., Garrett, T. E., Moore, C. J., Schwartz, K. M., Johnson, B. C., Craig, D., Salem, M. L., Paulos, C. M., & Cole, D. J. (2012) · Journal of the American College of Surgeons · doi:10.1016/j.jamcollsurg.2011.12.034 · Cited by 38
Lebrun, A., Portocarrero, C. P., Kean, R. B., Barkhouse, D. A., Faber, M., & Hooper, D. C. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501274 · Cited by 38
Natural killer cell memory in context
Holmes, T. D., & Bryceson, Y. T. (2016) · Seminars in Immunology · doi:10.1016/j.smim.2016.05.008 · Cited by 40
Hosking, M., Flynn, C. T., & Whitton, J. L. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400348 · Cited by 38
“More generally, strong inflammatory signals, such as IL-12 or CpG, promote T-bet expression, and reciprocally repress Eomes (37, 38), and the relative level of T-bet versus Eomes expression determines whether an effector T cell will become a shortlived effector cell or a memory precursor effector cell (39, 40).”
BackgroundIL-12 Signals through the TCR To Support CD8 Innate Immune Responses
Goplen, N., Saxena, V., Knudson, K. M., Schrum, A. G., Gil, D., Daniëls, M. A., Zamoyska, R., & Teixeiro, E. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600037 · Cited by 37
AMPK in Lymphocyte Metabolism and Function
Andris, F., & Léo, O. (2014) · International Reviews of Immunology · doi:10.3109/08830185.2014.969422 · Cited by 38
“In support of this contention, inhibition of mTORC1 signaling via rapamycin treatment during the contraction phase of a viral infection accelerates the transition towards CD8+ memory cells and increases the number of long-term functional memory T cells [26,68].”
BackgroundZhou, L., He, X., Cai, P., Li, T., Peng, R., Dang, J., Li, Y., Li, H., Huang, F., Shi, G., et al. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-00623-2 · Cited by 38
EOMES‐positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers
Chemin, K., Ramsköld, D., Díaz-Gallo, L.-M., Herrath, J., Houtman, M., Tandre, K., Rönnblom, L., Catrina, A. I., & Malmström, V. (2018) · European Journal of Immunology · doi:10.1002/eji.201747296 · Cited by 40
PI3Kδ Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes
Pearce, V. Q., Bouabe, H., MacQueen, A. R., Carbonaro, V., & Okkenhaug, K. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501227 · Cited by 36
“Similarly, the inhibition of mammalian target of rapamycin (mTOR) has been shown to favor the formation of CD8 Tmem via differential regulation of T-bet and Eomes (23, 24).”
BackgroundInfluentialSignal 3 requirement for memory CD8+ T‐cell activation is determined by the infectious pathogen
Keppler, S. J., & Aichele, P. (2011) · European Journal of Immunology · doi:10.1002/eji.201141537 · Cited by 35
Heterogeneity within T Cell Memory: Implications for Transplant Tolerance
Krummey, S. M., & Ford, M. L. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00036 · Cited by 36
“…contraction of CD8+ effector T cell populations, as evidenced by the increased differentiation of memory CD8+ T cells in both Tbet−/− and BLIMP−/− animals (Intlekofer et al., 2005; Joshi et al., 2007; Kallies et al., 2009; Rutishauser et al., 2009; Shin et al., 2009; Welsh, 2009; Rao et al., 2010).”
BackgroundRousseau, B., Guillemin, A., Duvoux, C., Neuzillet, C., Tlemsani, C., Compagnon, P., Azoulay, D., Salloum, C., Laurent, A., TAILLE, A. D. L., et al. (2018) · International Journal of Cancer · doi:10.1002/ijc.31769 · Cited by 36
Metadata
- Authors
- Rao, R. R., Li, Q., Odunsi, K., & Shrikant, P. A.
- Affiliations
- Roswell Park Comprehensive Cancer Center (US)
- Corresponding author
- Shrikant, Protul A.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 32
- Issue
- 1
- Pages
- 67-78
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5836496
- OpenAlex
- W2059689009
- Cited by
- 656
- References
- 41
- Citations by year
- 2026: 15 · 2025: 23 · 2024: 15 · 2023: 24 · 2022: 41 · 2021: 40 · 2020: 36 · 2019: 38 · 2018: 44 · 2017: 39 · 2016: 43 · 2015: 63 · 2014: 49 · 2013: 66 · 2012: 54
- FWCI
- 25.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA158318, R01CA104645, P30CA016056)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mTOR kinase, CD8+ T cells, T-bet, Eomesodermin, IL-12, phosphatidylinositol 3-kinase, STAT4, rapamycin, naive T cell differentiation, cancer immunotherapy
- MeSH terms
- T-bet Transcription Factor, Animals, Cell Differentiation, Immunologic Memory, Lymphocyte Activation, Mice, Transgenic, Transduction, Genetic, Signal Transduction, T-Lymphocyte Subsets, Protein Serine-Threonine Kinases, CD8-Positive T-Lymphocytes, T-Box Domain Proteins, Intracellular Signaling Peptides and Proteins, Mice, TOR Serine-Threonine Kinases
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