Natural killer cell-dependent apoptosis of peripheral murine hematopoietic progenitor cells in response to Fas cross-linking: involvement of tumor necrosis factor-alpha.
Recently, a marked extramedullary myelopoiesis in Fas/CD95- or FasL/CD95L-deficient mice has been reported. In the present in vitro study, the mechanisms underlying Fas-induced apoptosis of normal peripheral colony-forming unit-C (CFU-C) progenitors in the spleen were analyzed. Surprisingly, it was found that clonogenic progenitors were protected from gammaIFN plus Fas-induced programmed cell death when Lin(+) cells were removed from cultured splenocytes. The cells that rendered CFU-C sensitive to the activation of the Fas pathway did not belong to the T or the myelocytic-monocytic lineage but comprised a non-B-cell subset expressing the activation marker B220. Among CD19(-) B220(+) splenocytes, nearly half were natural killer (NK) 1.1(+) cells whose in vivo depletion or deficiency in RAG2-gamma(c)(-/-) mice abrogated the effect of Fas cross-linking. NK cells exerted their accessory function, at least in part, through tumor necrosis factor-alpha (TNF-alpha), which they readily produced during pretreatment with the anti-Fas/CD95 monoclonal antibody and IFN-gamma and whose addition could compensate for the loss of sensitivity. In conclusion, this study provides evidence that peripheral clonogenic progenitors are not directly responsive to Fas cross-linking, even in the presence of IFN-gamma, but require NK cells as a source of TNF-alpha to make them susceptible to this death pathway.
Moreau
G
G
CNRS UMR 8603, Université René Descartes-Paris V, Hôpital Necker, Paris, France.
Leite-De-Moraes
M
M
Ezine
S
S
Di Santo
J P
JP
Dy
M
M
Schneider
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018941:Antigens, CD19 / Q000032:analysis; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002469:Cell Separation; D002999:Clone Cells / Q000166:cytology; D003432:Cross-Linking Reagents; D006411:Hematopoiesis, Extramedullary; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D003432:Cross-Linking Reagents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases