NEUTRALIZATION OF TUMOR-NECROSIS-FACTOR ACTIVITY SHORTLY AFTER THE ONSET OF DENDRITIC CELL HEMATOPOIESIS REVEALS A NOVEL MECHANISM FOR THE SELECTIVE EXPANSION OF THE CD14-DEPENDENT DENDRITIC CELL PATHWAY

The CD14-dependent and -independent dendritic cell (DC) pathways are i nstituted simultaneously when CD34(+) progenitor cells are treated wit h granulocyte-macrophage colony-stimulating factor (GM-CSF)/tumor necr osis factor (TNF) +/- stem cell factor (SCF) (GTS). If TNF activity is neutralized within 48 hours of cytokine exposure, DC development is h alted and myelogranulocytic hematopoiesis takes place. In this study, we show that disruption of TNF activity at a later time point produced a distinct alteration within the DG system. Instead of downregulating DC development, treatment of GTS cultures with antibodies to TNF (ant i-TNF) on day 3 provoked the selective expansion of the CD14-dependent (monocyte) DC pathway from progenitor cell populations lacking CD14 a nd CD1a, After an initial decrease in proliferation, anti-TNF produced a rebound in cell growth that yielded intermediate myeloid progenitor s exhibiting CD14-dependent DC differentiation potential and CD14(+)CD 1a(+) DC precursors. Cultures enriched in CD14-dependent DCs were more potent stimulators of a mixed leukocyte reaction, compared with contr ol GTS cultures containing both types of DCs. The intermediate progeni tors expanded in the presence of anti-TNF were CD115(+)CD33(+)DR(+), l ong-lived, and displayed clonogenic potential in methylcellulose. When exposed to the appropriate cytokine combinations, these cells yielded granulocytes, monocytes, and CD14-dependent DCs. Antigen-presenting f unction was acquired only when DC maturation was induced from these my elodendritic progenitors with GM-CSF + interleukin-4 or GTS. These stu dies show a novel mechanism by which TNF regulates the DC system, as w ell as providing a strategy for the amplification of the CD14-dependen t DC pathway from immature progenitors. Although TNF is required to en sure the institution of DC hematopoiesis from CD34(+) progenitor cells , its activity on a later progenitor appears to limit the development of CD14-dependent DCs. (C) 1998 by The American Society of Hematology.