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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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BackgroundInfluential
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“…activity blocked Tbet expression and promoted elevated and sustained levels of the closely related T-bet transcription factor eomesodermin (Eomes) that is associated with the development of memory T cells (Pearce et al., 2003; Intlekofer et al., 2005, 2008; Joshi et al., 2005; Rao et al., 2010).”
BackgroundInfluentialTCR Signaling in T Cell Memory
Daniëls, M. A., & Teixeiro, E. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00617 · Cited by 111
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“In normal T cells, sustained mTOR activation leads to terminal differentiation, as well as induction of T-bet and repression of Eomes expression.(22,37,38) Such cells show reduced proliferative capacity and defective memory formation.”
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BackgroundmTOR, linking metabolism and immunity
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“In contrast, Eomesodermin expression was required for the development of memory cells with the long-term survival capacity (35,38).”
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BackgroundRegulation of T‐cell survival and mitochondrial homeostasis by TSC1
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BackgroundmTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics
Zhang, H., Xiao, X., Pan, Z., & Dokudovskaya, S. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02493-4 · Cited by 94
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“More recent studies have indicated that the mTOR pathway regulates generation of effector T cells and regulatory T cells (23, 24).”
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Architects of immunity: How dendritic cells shape CD8 + T cell fate in cancer
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“For instance, transcription factors Eomes and Bcl6 promote the generation of MPECs, whereas Blimp1 and T-bet drive the transcriptional programs for SLEC differentiation (1).”
BackgroundInfluentialChimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges
Han, E. Q., Li, X., Wang, C., Li, T.-F., & Han, S. (2013) · Journal of Hematology & Oncology · doi:10.1186/1756-8722-6-47 · Cited by 79
“Wnt-β-catenin pathways [36].”
Rise of the natural red pigment ‘prodigiosin’ as an immunomodulator in cancer
Anwar, M. M., Albanese, C., Hamdy, N. Μ., & Sultan, A. S. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02815-4 · Cited by 81
Immunometabolism of T cells and NK cells: metabolic control of effector and regulatory function
Poznanski, S. M., Barra, N. G., Ashkar, A. A., & Schertzer, J. D. (2018) · Inflammation Research · doi:10.1007/s00011-018-1174-3 · Cited by 78
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mTOR Links Environmental Signals to T Cell Fate Decisions
Chapman, N. M., & Chi, H. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00686 · Cited by 76
“PI3K or mTORC1 inhibition in activated CD8 T cells reduces IL-2-induced downregulation of CCR7, CD62L, and S1PR1 expression (136), which causes these cells to traffic to lymph nodes (34).”
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“transcription factors T-bet and Eomesodermin (Eomes) play key roles (Intlekofer et al., 2005; Rao et al., 2010).”
BackgroundmTOR co-targeting strategies for head and neck cancer therapy
Wang, Z., Valera, J. L. C., Zhao, X., Chen, Q., & Gutkind, J. S. (2017) · Cancer and Metastasis Reviews · doi:10.1007/s10555-017-9688-7 · Cited by 79
Paradoxical Aspects of Rapamycin Immunobiology in Transplantation
Ferrer, I. R., Araki, K., & Ford, M. L. (2011) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03473.x · Cited by 75
“Another possible mechanism by which rapamycin may augment the generation of T cell memory is by impacting the relative balance of expression of the transcription factors T-bet and Eomesodermin in CD8+ T cells (14).”
BackgroundThe metabolic spectrum of memory T cells
O’Sullivan, D. (2019) · Immunology and Cell Biology · doi:10.1111/imcb.12274 · Cited by 80
Generation, persistence and plasticity of CD4 T‐cell memories
Lees, J. R., & Färber, D. L. (2010) · Immunology · doi:10.1111/j.1365-2567.2010.03288.x · Cited by 75
Early events governing memory CD8+ T-cell differentiation
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Connecting the mechanisms of T‐cell regulation: dendritic cells as the missing link
Cobbold, S. P., Adams, E., Nolan, K. F., Regateiro, F. S., & Waldmann, H. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00913.x · Cited by 74
“mTOR activation has been demonstrated to be important for the generation of CD8 effector cytotoxic T-lymphocytes (78), while inhibition of mTOR in T cells has been previously linked to the enhancement of memory CD8 T cells (79, 80), the inhibition of T-cell trafficking from lymph nodes via the S1P receptor (81), and t…”
BackgroundNK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation
Yang, M., Chen, S., Du, J., He, J., Wang, Y., Li, Z., Liu, G., Peng, W., Zeng, X., Li, D., et al. (2016) · Nature Communications · doi:10.1038/ncomms12730 · Cited by 73
The Role of Tuberous Sclerosis Complex 1 in Regulating Innate Immunity
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CXCR5+CD8+ T cells are a distinct functional subset with an antitumor activity
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CD 8+ T‐cell effector function and transcriptional regulation during HIV pathogenesis
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“Eomes Cytotoxicity generation, granzyme and perforin production, expression of IL-15 receptor (CD122), upregulation of exhaustion markers (169, 171, 172, 174, 181, 187)”
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“We find that, contrary to what has been described for high-affinity ligands (Rao et al., 2010), high IL-12 does not repress Eomes for low-affinity ligands and, actually, has the opposite effect at low antigen doses.”
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“Interestingly, several studies demonstrate that rapamycin enhanced the survival of activated T cells [26,27,28,29,30] and generation of long-lived memory T cells [19,31,32].”
BackgroundAutophagy Modulation for Alzheimer’s Disease Therapy
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Christopoulos, P., Engel-Riedel, W., Grohé, C., Kropf-Sanchen, C., von Pawel, J., Gutz, S., Kollmeier, J., Eberhardt, W., Ukena, D., Baum, V., et al. (2017) · Annals of Oncology · doi:10.1093/annonc/mdx268 · Cited by 67
“Although classically viewed as an immunosuppressant and used to prevent graft rejection after transplantation [16], recent studies show that mTOR inhibition also enhances CD8þ T-cell mediated tumor immunity [17] and improves immune function in the elderly [18].”
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“Notably, recent clinical studies have associated rapalogs with active antitumor immune responses via promoting CD8þ memory T cells (48, 49).”
BackgroundWei, X., Ai, K., Li, H., Zhang, Y., Li, K., & Yang, J. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900008 · Cited by 65
“In turn, mTORC1 and its tight regulation are required for proper T cell activation (18), effector CD8 T cell expansion and memory CD8 T cell formation (23, 24), CD4 Th cell differentiation (25–27), induced regulatory T cell function (28), and invariant NKT maturation (29, 30).”
BackgroundCombining cancer immunotherapy and targeted therapy
Ribas, A., & Wolchok, J. D. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.02.011 · Cited by 64
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“Recent studies suggest that the enhancing mTOR activity may improve the effect of T cells by up-regulating T-bet [52, 53].”
BackgroundNK Cell Maturation and Function in C57BL/6 Mice Are Altered by Caloric Restriction
Clinthorne, J. F., Beli, E., Duriancik, D. M., & Gardner, E. M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1201837 · Cited by 64
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“It is noteworthy that it was recently reported in a mouse model that mTOR blockade with rapamycin leads to the generation of memory transgenic T cells (OVA-specific OT-1 cells) that were more efficient in generating tumor immunity than the IL-12-conditioned type I effector T cells considered to be the strongest induce…”
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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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