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
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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U2 - 10.26508/lsa.201800282
DO - 10.26508/lsa.201800282
M3 - Article
C2 - 30683688
AN - SCOPUS:85060777234
SN - 2575-1077
VL - 2
JO - Life Science Alliance
JF - Life Science Alliance
IS - 1
M1 - e201800282
ER -