Crosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function

Fangjie Wang, Meng Meng, Banghui Mo, Yao Yang, Yan Ji, Pei Huang, Wenjing Lai, Xiaodong Pan, Tingting You, Hongqin Luo, Xiao Guan, Yafei Deng, Shunzong Yuan, Jianhong Chu, Michael Namaka, Tiffany Hughes, Lilin Ye, Jianhua Yu, Xiaohui Li () and Youcai Deng ()
Additional contact information
Fangjie Wang: Army Medical University (Third Military Medical University)
Meng Meng: Army Medical University (Third Military Medical University)
Banghui Mo: Army Medical University (Third Military Medical University)
Yao Yang: Army Medical University (Third Military Medical University)
Yan Ji: Army Medical University (Third Military Medical University)
Pei Huang: Army Medical University (Third Military Medical University)
Wenjing Lai: Army Medical University (Third Military Medical University)
Xiaodong Pan: Army Medical University (Third Military Medical University)
Tingting You: Army Medical University (Third Military Medical University)
Hongqin Luo: Army Medical University (Third Military Medical University)
Xiao Guan: Army Medical University (Third Military Medical University)
Yafei Deng: Army Medical University (Third Military Medical University)
Shunzong Yuan: PLA 307 Hospital
Jianhong Chu: Soochow University
Michael Namaka: Army Medical University (Third Military Medical University)
Tiffany Hughes: The Ohio State University Comprehensive Cancer Center and the James Cancer Hospital
Lilin Ye: Army Medical University (Third Military Medical University)
Jianhua Yu: The Ohio State University Comprehensive Cancer Center and the James Cancer Hospital
Xiaohui Li: Army Medical University (Third Military Medical University)
Youcai Deng: Army Medical University (Third Military Medical University)

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract The metabolic checkpoint kinase mechanistic/mammalian target of rapamycin (mTOR) regulates natural killer (NK) cell development and function, but the exact underlying mechanisms remain unclear. Here, we show, via conditional deletion of Raptor (mTORC1) or Rictor (mTORC2), that mTORC1 and mTORC2 promote NK cell maturation in a cooperative and non-redundant manner, mainly by controlling the expression of Tbx21 and Eomes. Intriguingly, mTORC1 and mTORC2 regulate cytolytic function in an opposing way, exhibiting promoting and inhibitory effects on the anti-tumor ability and metabolism, respectively. mTORC1 sustains mTORC2 activity by maintaining CD122-mediated IL-15 signaling, whereas mTORC2 represses mTORC1-modulated NK cell effector functions by restraining STAT5-mediated SLC7A5 expression. These positive and negative crosstalks between mTORC1 and mTORC2 signaling thus variegate the magnitudes and kinetics of NK cell activation, and help define a paradigm for the modulation of NK maturation and effector functions.

Date: 2018
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DOI: 10.1038/s41467-018-07277-9

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