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

2 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 languageEnglish (US)
Article numbere201800282
JournalLife Science Alliance
Volume2
Issue number1
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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ASJC Scopus subject areas

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

Cite this

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. (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