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

Fangjie Wang,Tiffany Hughes,Xiaohui Li,Banghui Mo,Pei Huang,Xiaodong Pan,Lilin Ye,Hongqin Luo,Xiao Guan,Wenjing Lai,Jianhua Yu,Yafei Deng,Tianyan You ,Shunzong Yuan,Meng Meng,Yao Yang,Jing Yan ,Jianhong Chu,Michael Namaka,Youcai Deng

doi:10.1038/s41467-018-07277-9

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.

Highlights

The metabolic checkpoint kinase mechanistic/mammalian target of rapamycin regulates natural killer (NK) cell development and function, but the exact underlying mechanisms remain unclear
We demonstrate that mTORC1 sustains mTORC2 activity by maintaining CD122-mediated IL-15 signaling, whereas mTORC2 represses mTORC1 by controlling Natural killer (NK) cell effector functions mainly through restraining STAT5-mediated SLC7A5 expression
We identified the critical roles of mTORC1 and mTORC2 in regulating NK cell development and effector functions

Summary

Introduction

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. MTORC1 sustains mTORC2 activity by maintaining CD122-mediated IL-15 signaling, whereas mTORC2 represses mTORC1-modulated NK cell effector functions by restraining STAT5mediated SLC7A5 expression. Recent studies involving rapamycin treatment or mTOR deletion indicate that the kinase mTOR controls a key checkpoint in NK cell differentiation and activation that occurs downstream of IL-15 and requires a negative signal from Tsc[112, 13]. We demonstrate that mTORC1 sustains mTORC2 activity by maintaining CD122-mediated IL-15 signaling, whereas mTORC2 represses mTORC1 by controlling NK cell effector functions mainly through restraining STAT5-mediated SLC7A5 expression. These findings bring new insights regarding the interplay that occurs among mTOR and STAT5 signaling in NK cells

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Results

Conclusion