Natural killer cell-dependent apoptosis of peripheral murine hematopoietic progenitor cells in response to Fas cross-linking: Involvement of tumor necrosis factor-α

Abstract

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 γIFN 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-γc-/- mice abrogated the effect of Fas cross-linking. NK cells exerted their accessory function, at least in part, through tumor necrosis factor-α (TNF-α), which they readily produced during pretreatment with the anti-Fas/CD95 monoclonal antibody and IFN-γ 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-γ, but require NK cells as a source of TNF-α to make them susceptible to this death pathway. © 2001 by The American Society of Hematology.