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

Meixiang Yang,Song Wang,Zhongjun Dong,Dan Li,Xiaokang Zeng,Yuande Wang,Wanwen Peng,Panglian Xu,Zhigang Tian,Guangao Liu,Zai Chang,Shasha Chen,Junming He,Wei Guo,Zehua Li,Juan Du

doi:10.1038/ncomms12730

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.

Highlights

Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development
The distal signalling downstream of PI3K activation activates mammalian target of rapamycin, which is a component of two active complexes, mTOR complex 1 and mTORC2. mTOR kinase has been reported to play a crucial role as a key metabolic checkpoint in NK cell proliferation and activation[18]
To investigate how IL-15-mediated signalling is negatively controlled, we measured the messenger RNA levels of several potential suppressors involved in the Janus kinase (JAK)-STAT pathway and PI3K/mTOR pathway in NK cells stimulated with a high dose of IL-15 for 18 h (h)

Summary

Introduction

Activation of metabolic signalling by IL-15 is required for natural killer (NK) cell development. 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. IL-15 signalling is thought to be involved in the maintenance of NK cell survival and homeostasis in peripheral immune niches This cytokine supports NK cell development and survival mainly through the activation of a FOXO-dependent transcriptional programme and the prevention of Bim-mediated apoptosis[3,4,5]. Mice lacking either phosphatase and tensin homologue deleted on chromosome 10 or Src homology 2 domain-containing inositol-5phosphatase-1 exhibit abnormal NK cell development and functionality, demonstrating the crucial roles of these two proteins in actively maintaining NK cell function[15,16,17]. It remains unknown whether Tsc[1] is necessary for restraining IL-15/mTOR signalling during NK cell development, homeostasis and functioning

Methods

Results

Conclusion