Interleukin-2-activated natural killer cells can support hematopoiesis in vitro and promote marrow engraftment in vivo.
Purified natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID) to ascertain their effect on hematopoiesis. When activated and propagated with recombinant human interleukin-2 (rhIL-2) in vitro, SCID spleen cells maintained a phenotypic and lytic spectrum consistent with a pure population of activated NK cells. When added with syngeneic bone marrow cells (BMC) in soft agar, the activated NK cells could support hematopoietic growth in vitro without the addition of exogenous hematopoietic growth factors. However, when syngeneic BMC were added along with cytokines to produce optimal growth conditions, the addition of NK cells was then inhibitory for hematopoietic colony formation. Antibodies to interferon-gamma (IFN-gamma) partially reversed the inhibitory effects. Supernatants from the NK-cell cultures could also exert these effects on hematopoiesis, although to a lesser extent. Analysis of the NK cell RNA demonstrated that activated NK cells express genes for hematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and IL-1 beta. The NK cells were also found to express IFN-gamma, transforming growth factor-beta 1 (TGF-beta 1), and tumor necrosis factor-alpha (TNF-alpha) mRNA. Analysis of the NK-cell supernatants using factor-dependent myeloid progenitor cell lines showed that the NK cells were producing G-CSF and growth-promoting activity that could not be attributed to IL-1, IL-3, IL-4, IL-5, IL-6, GM-CSF, G-CSF, macrophage CSF (M-CSF), or stem cell factor. The transfer of activated NK cells with BMC into lethally irradiated syngeneic mice resulted in greater BMC engraftment in the recipients. Thus, these results using a pure population of activated NK cells indicate that when activated, these cells can produce a variety of growth factors for hematopoiesis and exert significant hematopoietic growth-promoting effects in vivo.
Murphy
W J
WJ
Biological Response Modifiers Program, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201.
Keller
J R
JR
Harrison
C L
CL
Young
H A
HA
Longo
D L
DL
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D015342:DNA Probes; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006410:Hematopoiesis / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology*; D015847:Interleukin-4 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology* / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D016133:Polymerase Chain Reaction / Q000379:methods; D012313:RNA / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics*; D015375:Receptors, Interleukin-2 / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015342:DNA Probes; D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4; D012313:RNA; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor