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

Nat Commun. 2016 Sep 7:7:12730. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • B-Lymphocytes
  • Gene Expression Regulation / physiology
  • Hematopoiesis / physiology
  • Interleukin-15 / genetics
  • Interleukin-15 / metabolism*
  • Interleukin-2 Receptor beta Subunit / genetics
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Killer Cells, Natural / physiology*
  • Mechanistic Target of Rapamycin Complex 1 / genetics
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Melanoma, Experimental
  • Mice
  • Mice, Knockout
  • Protein Subunits
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • T-Lymphocytes
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Eomes protein, mouse
  • Il2rb protein, mouse
  • Interleukin-15
  • Interleukin-2 Receptor beta Subunit
  • Protein Subunits
  • T-Box Domain Proteins
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • Mechanistic Target of Rapamycin Complex 1