A potential role for interleukin-15 in the regulation of human natural killer cell survival.
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.
Carson
W E
WE
Division of Surgery, Roswell Park Cancer Center, Buffalo, New York 14263, USA.
Fehniger
T A
TA
Haldar
S
S
Eckhert
K
K
Lindemann
M J
MJ
Lai
C F
CF
Croce
C M
CM
Baumann
H
H
Caligiuri
M A
MA
D000818:Animals; D017209:Apoptosis; D001681:Biological Assay; D015152:Blotting, Northern; D015153:Blotting, Western; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D011419:Propidium; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019409:Interleukin-15; D007378:Interleukins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D011419:Propidium; D004247:DNA