The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
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
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787 · cited 3×
“It is possible that mTOR, which has been shown to tether several transcriptional factors (both activators and repressors) (Wullschleger et al., 2006) may regulate T-bet expression based on its activity.”
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.”
BackgroundA Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment
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×
“The transcription factor T-bet (Tbx21) is the master regulator of type I effector differentiation whose expression is considerably enhanced and sustained in the presence of IL-12 (Joshi et al., 2007; Szabo et al., 2000).”
BackgroundCancer regression in patients after transfer of genetically engineered lymphocytes
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×
“Rapamycin-Treated IL-12-Conditioned OT-I Cells Demonstrate Augmented Tumor Efficacy The use of ex vivo generated tumor-antigen-specific effector CD8 T cells in adoptive cell transfer (ACT) has produced tumor regressions in the clinical setting (Morgan et al., 2006).”
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×
“We performed phenotypic analysis of OT-I cells using markers associated with memory precursor CD8+ T cells, i.e., CD62L (lymph node homing) (Wherry et al., 2003), CD69 (lymph node retention) (Shiow et al., 2006), CD127 (IL-7Ra; essential for memory T cell maintenance) (Schluns et al., 2000), CD122…”
MethodJoshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861 · cited 9×
“Several transcription factors have been shown to coordinate and regulate the balance between long-lived memory and terminally differentiated effector CD8+ T cells (Intlekofer et al., 2005; Joshi et al., 2007; Welsh, 2009).”
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×
“…node homing) (Wherry et al., 2003), CD69 (lymph node retention) (Shiow et al., 2006), CD127 (IL-7Ra; essential for memory T cell maintenance) (Schluns et al., 2000), CD122 (IL-15Rb and essential for memory CD8+ T cell homeostatic renewal) (Schluns et al., 2002), KLRG1 (inversely corelated…”
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
Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y. (2009) · Nature · doi:10.1038/nature08097 · Cited by 1,559 · cited 6×
“…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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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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