2. Academic Validation
  3. Crosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function

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

  • Nat Commun. 2018 Nov 19;9(1):4874. doi: 10.1038/s41467-018-07277-9.
Fangjie Wang 1,  Meng Meng 1,  Banghui Mo 1,  Yao Yang 1,  Yan Ji 1,  Pei Huang 1,  Wenjing Lai 1,  Xiaodong Pan 1,  Tingting You 1,  Hongqin Luo 1,  Xiao Guan 1,  Yafei Deng 1,  Shunzong Yuan 2,  Jianhong Chu 3,  Michael Namaka 1 4,  Tiffany Hughes 5,  Lilin Ye 6,  Jianhua Yu 5 7,  Xiaohui Li 8,  Youcai Deng 9
Affiliations

Affiliations

  • 1 Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), 30# Gaotanyan Road, Shapingba District, Chongqing, 400038, China.
  • 2 Department of Laboratory Medicine, PLA 307 Hospital, Dongdajie 8, Fengtai District, Beijing, 100071, China.
  • 3 Institute of Blood and Marrow Transplantation, Soochow University, No. 199 Renai Road, Suzhou, 215123, China.
  • 4 Colleges of Pharmacy and Medicine, Rady Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada.
  • 5 The Ohio State University Comprehensive Cancer Center and the James Cancer Hospital, 460 West 12th Ave, BRT 816, Columbus, 43210, OH, USA.
  • 6 Institute of Immunology, Army Medical University (Third Military Medical University), 30# Gaotanyan Road, Shapingba District, Chongqing, 400038, China.
  • 7 Division of Hematology, Department of Internal Medicine, The Ohio State University, 460 West 12th Ave, BRT 816, Columbus, OH, 43210, USA.
  • 8 Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), 30# Gaotanyan Road, Shapingba District, Chongqing, 400038, China. [email protected].
  • 9 Institute of Materia Medica, College of Pharmacy, Army Medical University (Third Military Medical University), 30# Gaotanyan Road, Shapingba District, Chongqing, 400038, China. [email protected].
PMID: 30451838 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.

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