mTOR signaling promotes a robust and continuous production of IFN‐γ by human memory CD8+ T cells and their proliferation
Open accessAbstract
Human CD8+ T cells are functionally heterogeneous and can be divided into phenotypically and functionally distinct subsets according to CCR7 and CD45RA expression levels. Among these, CCR7 low CD45RA low effector memory CD8+ T cells (Tem) and CCR7 low CD45RA high CD8+ T cells, which are designated as Temra and considered to be terminally differentiated cells, are Ag‐experienced T cells but show different functionalities. Here, we show that, while Tem proliferate vigorously and produce IFN‐γ persistently and robustly, Temra proliferate poorly and lose the ability to produce IFN‐γ over time after TCR stimulation. Temra showed impaired cell growth upon TCR stimulation, which was associated with defective activation of the mammalian target of rapamycin (mTOR) signaling. Furthermore, rapamycin, an inhibitor of mTOR signaling, interfered with the robust and continuous proliferation of and IFN‐γ production by Tem at later time points after TCR stimulation. Thus, these data collectively indicate that activation of mTOR signaling is required for the robust functions of Tem cells in humans and suggest that defective mTOR signaling in Temra contributes to their functional impairment.
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No data exist on the in vivo outcomes of mTORi on IFN-γ signaling and function.
“Although the IFN-γ and the mTOR pathways seem to be tightly interwoven, no data exist on the in vivo outcomes of mTORi on IFN-γ signaling and function38–40.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [39]
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- Authors
- Setoguchi, R., Matsui, Y., & Mouri, K.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Setoguchi, Ruka
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2015-01-02
- Volume
- 45
- Issue
- 3
- Pages
- 893-902
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W1573179618
- Cited by
- 21
- References
- 34
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2016: 4
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- mTOR signaling, IFN-gamma production, CD8+ T cells, effector memory T cells, TEMRA cells, T cell proliferation, T cell receptor stimulation, rapamycin, CCR7, CD45RA, T cell differentiation
- MeSH terms
- Female, Humans, Immunologic Memory, Immunosuppressive Agents, Interferon-gamma, Male, Receptors, Antigen, T-Cell, Signal Transduction, Leukocyte Common Antigens, CD8-Positive T-Lymphocytes, Sirolimus, Cell Proliferation, Receptors, CCR7, TOR Serine-Threonine Kinases
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