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 journalArticle

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 languageEnglish
Article numbere201800282
JournalLife Science Alliance
Volume2
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

T-cells
interferons
Interferons
T-lymphocytes
Genes
Chemical activation
T-Lymphocytes
gene
genes
Interferon Type I
ligand
Cell growth
Pathogens
pathogen
mechanistic target of rapamycin complex 1
regulation
cell growth
DNA
Ligands
cyclic guanosine monophosphate-adenosine monophosphate

ASJC Scopus subject areas

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

Cite this

Imanishi, T., Unno, M., Kobayashi, W., Yoneda, N., Matsuda, S., Ikeda, K., ... Saito, T. (2019). Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function. Life Science Alliance, 2(1), [e201800282]. https://doi.org/10.26508/lsa.201800282

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 journalArticle

Imanishi, T, Unno, M, Kobayashi, W, Yoneda, N, Matsuda, S, Ikeda, K, Hoshii, T, Hirao, A, Miyake, K, Barber, GN, Arita, M, Ishii, KJ, Akira, S & Saito, T 2019, 'Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function', Life Science Alliance, vol. 2, no. 1, e201800282. https://doi.org/10.26508/lsa.201800282
Imanishi T, Unno M, Kobayashi W, Yoneda N, Matsuda S, Ikeda K et al. Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function. Life Science Alliance. 2019 Jan 1;2(1). e201800282. https://doi.org/10.26508/lsa.201800282
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{f6bb4fb7ed574205a39a64ff24f9a52f,
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",
year = "2019",
month = "1",
day = "1",
doi = "10.26508/lsa.201800282",
language = "English",
volume = "2",
journal = "Life Science Alliance",
issn = "2575-1077",
publisher = "Rockefeller University Press",
number = "1",

}

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 -