Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

Takayuki Imanishi; Midori Unno; Wakana Kobayashi; Natsumi Yoneda; Satoshi Matsuda; Kazutaka Ikeda; Takayuki Hoshii; Atsushi Hirao; Kensuke Miyake; Glen N. Barber; Makoto Arita; Ken J. Ishii; Shizuo Akira; Takashi Saito

doi:10.26508/lsa.201800282

Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

Takayuki Imanishi, Midori Unno, Wakana Kobayashi, Natsumi Yoneda, Satoshi Matsuda, Kazutaka Ikeda, Takayuki Hoshii, Atsushi Hirao, Kensuke Miyake, Glen N. Barber, Makoto Arita, Ken J. Ishii, Shizuo Akira, Takashi Saito

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

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	https://doi.org/10.26508/lsa.201800282
State	Published - 2019
Externally published	Yes

ASJC Scopus subject areas

Ecology
Biochemistry, Genetics and Molecular Biology (miscellaneous)
Plant Science
Health, Toxicology and Mutagenesis

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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, 2019.

Research output: Contribution to journal › Article › peer-review

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. / Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function. In: Life Science Alliance. 2019 ; Vol. 2, No. 1.

@article{fc03e143934c4cecae08f54f77107145,

title = "Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function",

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.",

author = "Takayuki Imanishi and Midori Unno and Wakana Kobayashi and Natsumi Yoneda and Satoshi Matsuda and Kazutaka Ikeda and Takayuki Hoshii and Atsushi Hirao and Kensuke Miyake and Barber, {Glen N.} and Makoto Arita and Ishii, {Ken J.} and Shizuo Akira and Takashi Saito",

note = "Funding Information: We thank T Taniguchi for providing IRF3-KO, IRF7-KO, and IRF3/7-DKO mice; T Yokosuka, A Takeuchi, S Tsukumo, R Onishi, A Hashimoto-Tane, M Badr, N Hayatsu, H Ishigame, H Negishi, K Miyauchi, M Kubo, and H Hara for discussions and experimental help; M Sakuma for technical support; P Burrows for helpful comments on the manuscript; and M Yoshioka for secretarial assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science KAKENHI (grants 16K08852 for T Imanishi and 24229004 for T Saito). Publisher Copyright: {\textcopyright} 2019 Imanishi et al.",

year = "2019",

doi = "10.26508/lsa.201800282",

language = "English (US)",

volume = "2",

journal = "Life Science Alliance",

issn = "2575-1077",

publisher = "Rockefeller University Press",

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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

N1 - Funding Information: We thank T Taniguchi for providing IRF3-KO, IRF7-KO, and IRF3/7-DKO mice; T Yokosuka, A Takeuchi, S Tsukumo, R Onishi, A Hashimoto-Tane, M Badr, N Hayatsu, H Ishigame, H Negishi, K Miyauchi, M Kubo, and H Hara for discussions and experimental help; M Sakuma for technical support; P Burrows for helpful comments on the manuscript; and M Yoshioka for secretarial assistance. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science KAKENHI (grants 16K08852 for T Imanishi and 24229004 for T Saito). Publisher Copyright: © 2019 Imanishi et al.

PY - 2019

Y1 - 2019

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.

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DO - 10.26508/lsa.201800282

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AN - SCOPUS:85060777234

VL - 2

JO - Life Science Alliance

JF - Life Science Alliance

SN - 2575-1077

IS - 1

M1 - e201800282

ER -

Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function

Abstract

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