Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function
Open accessAbstract
Stimulator of interferon genes (STING) plays a key role in detecting cytosolic DNA and induces type I interferon (IFN-I) responses for host defense against pathogens. Although T cells highly express STING, its physiological role remains unknown. Here, we show that costimulation of T cells with the STING ligand cGAMP and TCR leads to IFN-I production and strongly inhibits T-cell growth. TCR-mediated mTORC1 activation and sustained activation of IRF3 are required for cGAMP-induced IFN-I production, and the mTORC1 activity is partially counteracted by cGAMP, thereby blocking proliferation. This mTORC1 inhibition in response to costimulation depends on IRF3 and IRF7. Effector T cells produce much higher IFN-I levels than innate cells in response to cGAMP. Finally, we demonstrated that STING stimulation in T cells is effective in inducing antitumor responses in vivo. Our studies demonstrate that the outputs of STING and TCR signaling pathways are mutually regulated through mTORC1 to modulate T-cell functions.
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Recent studies have indicated that STING agonist-induced T cell death depends on the type and doses of STING agonists.
“Although it was proposed that STING agonist can induce T cell death through the activation of proapoptotic transcriptional programs58, recent studies have indicated that this effect depends on the type and doses of STING agonists59,60.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [59]
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動作マージンを確保可能なディジタル LSI の製造後クロック調整手法の提案
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- Authors
- Imanishi, T., Unno, M., Kobayashi, W., Yoneda, N., Matsuda, S., Ikeda, K., Hoshii, T., Hirao, A., Miyake, K., Barber, G. N., Arita, M., Ishii, K. J., Akira, S., & Saito, T.
- Affiliations
- RIKEN Center for Integrative Medical Sciences (JP)
- Kansai Medical University (JP)
- Japan Agency for Medical Research and Development (JP)
- Kanazawa University (JP)
- Institute of Medical Science, The University of Tokyo (JP)
- University of Miami (US)
- Keio University (JP)
- National Institute of Biomedical Innovation, Health and Nutrition (JP)
- Immunology Frontier Research Center, The University of Osaka (JP)
- Corresponding author
- Imanishi, Takayuki
- Saito, Takashi
- ORCID
- Venue
- Life Science Alliance
- Publisher
- Life Science Alliance, LLC
- Published
- 2019-01-25
- Volume
- 2
- Issue
- 1
- Pages
- e201800282
- ISSN
- 2575-1077 (ISSN-L)
- PMC
- PMC6348487
- OpenAlex
- W2911294141
- Cited by
- 62
- References
- 46
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 7 · 2023: 13 · 2022: 12 · 2021: 9 · 2020: 6 · 2019: 1
- FWCI
- 2.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Life Science Alliance (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science KAKENHI (16K08852)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- STING, T cell receptor signaling, mTORC1, type I interferon, cGAMP, IRF3, IRF7, T cell proliferation, T cell costimulation, antitumor immunity, cytosolic DNA sensing, effector T cells
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, STING Protein, Animals, Interferon Type I, Lymphocyte Activation, Membrane Proteins, Mice, Inbred C57BL, Nucleotides, Cyclic, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, Mice, Knockout, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Mice, Cell Cycle Checkpoints, Heterografts
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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