Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function
Reciprocal regulation of STING and TCR signaling by mTORC1 for T-cell activation and function
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DOI：
10.26508/lsa.201800282
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发表时间：
2019-02-01
影响因子：
4.4
通讯作者：
Saito, Takashi
中科院分区：
文献类型：
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作者：
Imanishi, Takayuki;Unno, Midori;Saito, Takashi
干扰素基因刺激物(STINT)在检测胞浆DNA中起着关键作用，它能诱导I型干扰素(IFN-I)应答，以抵抗病原体。虽然T细胞高度表达STING，但其生理作用尚不清楚。在这里，我们展示了T细胞与刺激性配体cGAMP和TCR的共刺激导致干扰素-I的产生并强烈抑制T细胞的生长。CGAMP诱导的干扰素-I的产生需要TCR介导的mTORC1激活和IRF3的持续激活，cGAMP可以部分抵消mTORC1的活性，从而阻止细胞增殖。这种对共刺激反应的mTORC1抑制依赖于IRF3和IRF7。效应性T细胞在cGAMP刺激下产生的干扰素-I水平比天然细胞高得多。最后，我们证明了刺激性T细胞在体内诱导抗肿瘤反应是有效的。我们的研究表明，STING和TCR信号通路的输出通过mTORC1相互调节，从而调节T细胞的功能。
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.