Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | e201800282 |
| Journal | Life Science Alliance |
| Volume | 2 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Ecology
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- Plant Science
- Health, Toxicology and Mutagenesis
Cite this
Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function. / Imanishi, Takayuki; Unno, Midori; Kobayashi, Wakana; Yoneda, Natsumi; Matsuda, Satoshi; Ikeda, Kazutaka; Hoshii, Takayuki; Hirao, Atsushi; Miyake, Kensuke; Barber, Glen N; Arita, Makoto; Ishii, Ken J.; Akira, Shizuo; Saito, Takashi.
In: Life Science Alliance, Vol. 2, No. 1, e201800282, 01.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function
AU - Imanishi, Takayuki
AU - Unno, Midori
AU - Kobayashi, Wakana
AU - Yoneda, Natsumi
AU - Matsuda, Satoshi
AU - Ikeda, Kazutaka
AU - Hoshii, Takayuki
AU - Hirao, Atsushi
AU - Miyake, Kensuke
AU - Barber, Glen N
AU - Arita, Makoto
AU - Ishii, Ken J.
AU - Akira, Shizuo
AU - Saito, Takashi
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85060777234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060777234&partnerID=8YFLogxK
U2 - 10.26508/lsa.201800282
DO - 10.26508/lsa.201800282
M3 - Article
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
SN - 2575-1077
IS - 1
M1 - e201800282
ER -