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

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

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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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)
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
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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