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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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“Two, FOXO1 is essential for driving the memory program through direct induction of known targets Sell, Il7r, and of master transcription factors of memory such as Tcf7 and Eomes (Rao et al., 2010; Zhou et al., 2010).”
BackgroundInfluentialThe precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues
Kok, L., Masopust, D., & Schumacher, T. N. (2022) · Nature Reviews Immunology · doi:10.1038/s41577-021-00590-3 · Cited by 230
Targeting lysosomes in human disease: from basic research to clinical applications
Cao, M., Luo, X., Wu, K., & He, X. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00778-y · Cited by 225
Metabolism, migration and memory in cytotoxic T cells
Finlay, D. K., & Cantrell, D. A. (2011) · Nature reviews. Immunology · doi:10.1038/nri2888 · Cited by 227
“How could inhibition of mTORC1 with rapamycin or through activation of AMPK promote the transition of effector CTLs to memory CD8 + T cells? One explanation could be the ability of rapamycin to reprogramme the trafficking of effector CTLs such that these cells regain the ability to enter secondary lymphoid tissu”
BackgroundMetabolism of activated T lymphocytes
Maciolek, J. A., Pasternak, J. A., & Wilson, H. L. (2014) · Current Opinion in Immunology · doi:10.1016/j.coi.2014.01.006 · Cited by 232
“Further, long-lived CD8 memory T cells have substantial spare respiratory capacity after clearance of infection which is critical for producing sufficient ATP under times of stress and for boosting long-term cell survival [97,98].”
BackgroundmTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment
Mafi, S., Mansoori, B., Taeb, S., Sadeghi, H., Abbasi, R., Cho, W. C. S., & Rostamzadeh, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.774103 · Cited by 238
“However, several lines of evidence have identified that the mTOR inhibition promotes the development of memory CD8 T cells (13, 77, 81).”
BackgroundMetabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy
Gupta, S., Roy, A., & Dwarakanath, B. S. R. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00068 · Cited by 225
“It reduces glycolysis and increases lipid peroxidation through mTOR inhibition, enhances the formation of T memory cells (274), inhibits T-bet, a Th1-promoting transcription factor (275), and induces autophagy (276).”
BackgroundIborra, S., Martínez‐López, M., Khouili, S. C., Enamorado, M., Cueto, F. J., Conde‐Garrosa, R., del Fresno, C., & Sancho, D. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.019 · Cited by 224
“Notably, impaired crosspriming does not impact Eomes expression, which would explain the lack of an effect on circulating memory T cell gener- ation (Iborra et al., 2013; Joshi et al., 2007; Rao et al., 2010).”
InfluentialMa, R., Ji, T., Zhang, Y., Dong, W., Chen, X., Xu, P., Chen, D., Liang, X., Yin, X., Liu, Y., et al. (2017) · Nature Cell Biology · doi:10.1038/s41556-017-0002-2 · Cited by 211
Phan, A. T., Doedens, A. L., Palazón, A., Tyrakis, P. A., Cheung, K. P., Johnson, R. S., & Goldrath, A. W. (2016) · Immunity · doi:10.1016/j.immuni.2016.10.017 · Cited by 207
“…for various metabolic processes can have both deleterious or beneficial effects on effector and memory cell generation and survival (Chaoul et al., 2015; Cui et al., 2015; O’Sullivan et al., 2014; Okoye et al., 2015; Rao et al., 2010; Rolf et al., 2013; Sena et al., 2013; Shrestha et al., 2014).”
BackgroundInfluentialChimeric antigen receptor T cell persistence and memory cell formation
McLellan, A. D., & Rad, S. M. A. H. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12254 · Cited by 211
Regulation of T cells by mTOR: the known knowns and the known unknowns
Pollizzi, K. N., & Powell, J. D. (2014) · Trends in Immunology · doi:10.1016/j.it.2014.11.005 · Cited by 202
“Rapamycin treatment enhances quality and quantity of CD8+ T cell memory [56, 57, 61, 62].”
BackgroundmTOR signaling in the differentiation and function of regulatory and effector T cells
Zeng, H., & Chi, H. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.04.005 · Cited by 196
NFATc1 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
Keating, R., Hertz, T., Wehenkel, M., Harris, T. L., Edwards, B. A., McClaren, J. L., Brown, S. A., Surman, S. L., Wilson, Z., Bradley, P. H., et al. (2013) · Nature Immunology · doi:10.1038/ni.2741 · Cited by 197
Duraiswamy, J., Turrini, R., Minasyan, A., Barras, D., Crespo, I., Grimm, A. J., Casado, J., Genolet, R., Benedetti, F., Wicky, A. M., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2021.10.008 · Cited by 191
Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection
Tu, W., & Rao, S. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.02111 · Cited by 192
Bcl-6 directly represses the gene program of the glycolysis pathway
Oestreich, K. J., Read, K. A., Gilbertson, S. E., Hough, K. P., McDonald, P. W., Krishnamoorthy, V., & Weinmann, A. S. (2014) · Nature Immunology · doi:10.1038/ni.2985 · Cited by 192
mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions
Huang, H., Long, L., Zhou, P., Chapman, N. M., & Chi, H. (2020) · Immunological Reviews · doi:10.1111/imr.12845 · Cited by 193
Systemic 4-1BB activation induces a novel T cell phenotype driven by high expression of Eomesodermin
Curran, M. A., Geiger, T. L., Montalvo-Ortiz, W., Kim, M., Reiner, S. L., Al‐Shamkhani, A., Sun, J. C.-Y., & Allison, J. P. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121190 · Cited by 195
“…of Eomes as the master regulator in these KLRG1+ cytotoxic T cells, we sought to determine function had been described as the outcome of IL-12 production eliciting high levels of the T-box transcription factor T-bet, which in turn induced KLRG1 and higher Granzyme B expression (Rao et al., 2010).”
BackgroundRole of PI3K/Akt signaling in memory CD8 T cell differentiation
Kim, E. H., & Suresh, M. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00020 · Cited by 185
“By contrast, high levels of Eomes, Bcl-6, ID3, Mbd2, and Bmi-1 favor differentiation of MPECs (Rutishauser and Kaech, 2010).”
BackgroundInfluentialHeaden, D. M., Woodward, K. B., Coronel, M. M., Shrestha, P., Weaver, J. D., Zhao, H., Tan, M., Hunckler, M. D., Bowen, W. S., Johnson, C. T., et al. (2018) · Nature Materials · doi:10.1038/s41563-018-0099-0 · Cited by 175
Too Much of a Good Thing? Tim-3 and TCR Signaling in T Cell Exhaustion
Ferris, R. L., Lu, B., & Kane, L. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400557 · Cited by 171
“This was shown through the use of the relatively specific mTORC1 inhibitor rapamycin (54, 55) or by reducing expression of the Raptor gene, which encodes a critical subunit of the mTORC1 complex (54).”
Pathogen-Induced Inflammatory Environment Controls Effector and Memory CD8+ T Cell Differentiation
Obar, J. J., Jellison, E. R., Sheridan, B. S., Blair, D. A., Pham, Q.-M., Zickovich, J. M., & Lefrançois, L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102335 · Cited by 172
Avery, L., Filderman, J. N., Szymczak-Workman, A. L., & Kane, L. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1712107115 · Cited by 171
“Treatment of FSFTim3 mice with rapamycin throughout the course of LCMV-Arm infection reduced the KLRG1CD127 SLEC population, as was shown previously in normal mice, confirming that Tim-3 acts at least in part through mTOR (27, 31).”
BackgroundT‐bet and Eomes govern differentiation and function of mouse and human NK cells and ILC1
Zhang, J., Marotel, M., Fauteux‐Daniel, S., Mathieu, A., Viel, S., Marçais, A., & Walzer, T. (2018) · European Journal of Immunology · doi:10.1002/eji.201747299 · Cited by 182
Li, Q., Rao, R. R., Araki, K., Pollizzi, K. N., Odunsi, K. O., Powell, J. D., & Shrikant, P. A. (2011) · Immunity · doi:10.1016/j.immuni.2011.04.006 · Cited by 166
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Signal Integration by Akt Regulates CD8 T Cell Effector and Memory Differentiation
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“Seminal studies have demonstrated that cytokines such as IL-2 and IL-12 promote the differentiation of SLECs by inducing the transcription factor T-bet (4, 8, 11, 25).”
BackgroundInfluentialAdoptive immunotherapy for cancer
Ruella, M., & Kalos, M. D. (2013) · Immunological Reviews · doi:10.1111/imr.12136 · Cited by 160
“Modulation of the metabolic state of T cells has been shown to influence their phenotype and function; for example, modulation of PI3KAKT-mTOR and Wnt-b-catenin pathways had been shown to control the differentiation status of T cells; co-culture of T cells with mTor inhibitors promotes the formation of memory subsets,…”
BackgroundThe evolving role of tissue-resident memory T cells in infections and cancer
Yenyuwadee, S., Lopez, J. L. S.-T., Shah, R., Rosato, P. C., & Boussiotis, V. A. (2022) · Science Advances · doi:10.1126/sciadv.abo5871 · Cited by 162
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mTOR Signaling, Tregs and Immune Modulation
Chapman, N. M., & Chi, H. (2014) · Immunotherapy · doi:10.2217/imt.14.84 · Cited by 148
Metabolic challenges and interventions in CAR T cell therapy
Peng, J.-J., Wang, L., Li, Z., Ku, C., & Ho, P. (2023) · Science Immunology · doi:10.1126/sciimmunol.abq3016 · Cited by 156
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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