A potential role for interleukin-15 in the regulation of human natural killer cell survival

J Clin Invest. 1997 Mar 1;99(5):937-43. doi: 10.1172/JCI119258.


Resting lymphocyte survival is dependent upon the expression of Bcl-2, yet the factors responsible for maintaining lymphocyte Bcl-2 protein expression in vivo are largely unknown. Natural killer (NK) cells are bone marrow-derived lymphocytes that constitutively express the beta and common gamma(c) subunits of the IL-2 receptor (R) as a heterodimer with intermediate affinity for IL-2. IL-15 also binds to IL-2Rbeta gamma(c) and is much more abundant in normal tissues than IL-2. Mice that lack the IL-2 gene have NK cells, whereas mice and humans that lack IL-2R gamma(c) do not have NK cells. Further, treatment of mice with an antibody directed against IL-2Rbeta results in a loss of the NK cell compartment. These data suggest that a cytokine other than IL-2, which binds to IL-2Rbeta gamma(c), is important for NK cell development and survival in vivo. In the current report, we show that the recently described IL-15R(alpha) subunit cooperates with IL-2Rbeta gamma(c) to transduce an intracellular signal at picomolar concentrations of IL-15. We demonstrate that resting human NK cells express IL-15R(alpha) mRNA and further, that picomolar amounts of IL-15 can sustain NK cell survival for up to 8 d in the absence of serum. NK cell survival was not sustained by other monocyte-derived factors (i.e., TNF-alpha, IL-1beta, IL-10, IL-12) nor by cytokines known to use gamma(c) for signaling (i.e., IL-4, IL-7, IL-9, IL- 13). One mechanism by which IL-15 promotes NK cell survival may involve the maintenance of Bcl-2 protein expression. Considering these functional properties of IL-15 and the fact that it is produced by bone marrow stromal cells and activated monocytes, we propose that IL-15 may function as an NK cell survival factor in vivo.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Biological Assay
  • Blotting, Northern
  • Blotting, Western
  • Cell Survival*
  • DNA / metabolism
  • Flow Cytometry
  • Gene Expression Regulation
  • Humans
  • Interleukin-15 / pharmacology*
  • Interleukins / pharmacology
  • Killer Cells, Natural / metabolism*
  • Killer Cells, Natural / physiology*
  • Mice
  • Propidium
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / analysis
  • RNA, Messenger / biosynthesis
  • Receptors, Interleukin / biosynthesis*
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / physiology*
  • Receptors, Interleukin-2 / genetics
  • Receptors, Interleukin-2 / physiology
  • Signal Transduction
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology


  • Interleukin-15
  • Interleukins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Receptors, Interleukin
  • Receptors, Interleukin-2
  • Tumor Necrosis Factor-alpha
  • Propidium
  • DNA