The receptor tyrosine kinase c-kit provides a critical signal for survival, expansion, and maturation of mouse natural killer cells.
Fetal liver kinase ligands (flk2L/flt3L) and stem cell factor (SCF) have been shown to promote natural killer (NK) cell differentiation from hematopoietic stem cell (HSC) precursors in vitro. However, the contribution of signaling through the receptors for these growth factors for in vivo NK cell development remains ill-defined. We have analyzed the role of the SCF receptor c-kit in NK cell differentiation by reconstituting NK-deficient mice with fetal liver (FL) HSCs of c-kit(-/-) (W/W) mice. Although c-kit(-/-)NK cells were generated in W/W chimeras, they were reduced in number, contained a lower percentage of CD45R (B220)(+) cells, and were poorly cytolytic. In vitro experiments showed that generation of NK cells from FL precursors was reduced in the absence of c-kit signaling and that SCF promoted the survival of peripheral c-kit(+) NK cells. We conclude that c-kit/SCF interactions in vivo are dispensable for the commitment of HSC to the NK lineage, but they provide essential signals for generating normal numbers of fully mature NK cells.
Colucci
F
F
Institut National de la Santè et de la Recherche Medicale (INSERM) U429, Hôpital Necker-Enfants Malades, Paris, France.
Di Santo
J P
JP
D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D016175:B-Lymphocyte Subsets / Q000166:cytology; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D016332:Fetal Tissue Transplantation; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000196:embryology; D016031:Liver Transplantation; D018655:Lymphocyte Count; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D019089:Stem Cell Factor / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; C499308:Rag2 protein, mouse; D019089:Stem Cell Factor; C064655:V(D)J recombination activating protein 2; C084881:flt3 ligand protein; D019009:Proto-Oncogene Proteins c-kit