NK cell development requires Tsc1-dependent negative regulation of IL-15-triggered mTORC1 activation

Meixiang Yang, Shasha Chen, Juan Du, Junming He, Yuande Wang, Zehua Li, Guangao Liu, Wanwen Peng, Xiaokang Zeng, Dan Li, Panglian Xu, Wei Guo, Zai Chang, Song Wang, Zhigang Tian and Zhongjun Dong ()
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Meixiang Yang: Institute for Immunology and School of Medicine, Tsinghua University
Shasha Chen: Institute for Immunology and School of Medicine, Tsinghua University
Juan Du: Institute for Immunology and School of Medicine, Tsinghua University
Junming He: Biomedical Translational Research Institute, Jinan University
Yuande Wang: Biomedical Translational Research Institute, Jinan University
Zehua Li: Institute for Immunology and School of Medicine, Tsinghua University
Guangao Liu: Biomedical Translational Research Institute, Jinan University
Wanwen Peng: Biomedical Translational Research Institute, Jinan University
Xiaokang Zeng: Biomedical Translational Research Institute, Jinan University
Dan Li: Institute for Immunology and School of Medicine, Tsinghua University
Panglian Xu: School of Medicine, Tsinghua University
Wei Guo: School of Medicine, Tsinghua University
Zai Chang: Center of Animal Facility, Tsinghua University
Song Wang: Collaborative Innovation Center, Wuhan Sports University
Zhigang Tian: School of Life Sciences, University of Sciences and Technology of China
Zhongjun Dong: Institute for Immunology and School of Medicine, Tsinghua University

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. Here we show that Tsc1, a repressor of mTOR, is dispensable for the terminal maturation, survival and function of NK cells but is critical to restrict exhaustive proliferation of immature NK cells and activation downstream of IL-15 during NK cell development. Tsc1 is expressed in immature NK cells and is upregulated by IL-15. Haematopoietic-specific deletion of Tsc1 causes a marked decrease in the number of NK cells and compromises rejection of ‘missing-self’ haematopoietic tumours and allogeneic bone marrow. The residual Tsc1-null NK cells display activated, pro-apoptotic phenotype and elevated mTORC1 activity. Deletion of Raptor, a component of mTORC1, largely reverses these defects. Tsc1-deficient NK cells express increased levels of T-bet and downregulate Eomes and CD122, a subunit of IL-15 receptor. These results reveal a role for Tsc1-dependent inhibition of mTORC1 activation during immature NK cell development.

Date: 2016
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DOI: 10.1038/ncomms12730

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