Cited by 656T-cell and B-cell ImmunologyImmunotherapy and Immune ResponsesPI3K/AKT/mTOR signaling in cancer

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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

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Rao, Rajesh R., Li, Qingsheng, Odunsi, Kunle, Shrikant, Protul A.·2010·Immunity

DOI 10.1016/j.immuni.2009.10.010PMC PMC5836496

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Abstract

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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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×
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BackgroundInfluential
Upstream and downstream of mTOR
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“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.”
Background
A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment
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Background
Cancer 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).”
Background
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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.”
Background
Lineage 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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Method
Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-bet Transcription Factor
Joshi, 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).”
BackgroundInfluential
Interleukin-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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Background
mTOR 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
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BackgroundInfluential

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Lithium induces c-Ret expression in mouse inner medullary collecting duct cells
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BackgroundInfluential
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Background
MYO1F regulates T-cell activation and glycolytic metabolism by promoting the acetylation of GAPDH
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Background
Differential requirements for IRF4 in the clonal expansion and homeostatic proliferation of naive and memory murine CD8+ T cells
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IL-12 Influence mTOR to Modulate CD8+ T Cells Differentiation through T-bet and Eomesodermin in Response to Invasive Pulmonary Aspergillosis
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Viral Factors in Modulation of Host Immune Response: A Route to Novel Antiviral Agents and New Therapeutic Approaches
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Background
Stimulation through very late antigen‐4 and ‐5 improves the multifunctionality and memory formation of CD8+ T cells
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BackgroundResultInfluential
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Background
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Authors: Rao, R. R., Li, Q., Odunsi, K., & Shrikant, P. A.
Affiliations: Roswell Park Comprehensive Cancer Center (US)
Corresponding author: Shrikant, Protul A.
ORCID: Li, Qingsheng
Odunsi, Kunle
Venue: Immunity
Publisher: Elsevier BV
Published: 2010-01
Volume: 32
Issue: 1
Pages: 67-78
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2009.10.010
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
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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The mTOR Kinase Determines Effector versus Memory CD8+ T Cell Fate by Regulating the Expression of Transcription Factors T-bet and Eomesodermin

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