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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 745-755
RAPID COMMUNICATION
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
Frances Santiago-Schwarz,
Marguerite McCarthy,
John Tucci, and
Steven E. Carsons
From the Division of Rheumatology, Allergy and Immunology, Winthrop
University Hospital, Mineola, NY; and the Department of Medicine, State
University of New York at Stony Brook.
The CD14-dependent and -independent dendritic cell (DC) pathways are
instituted simultaneously when CD34+ progenitor cells are
treated with granulocyte-macrophage colony-stimulating factor
(GM-CSF)/tumor necrosis factor (TNF) ± stem cell factor (SCF) (GTS).
If TNF activity is neutralized within 48 hours of cytokine exposure, DC
development is halted 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 DC system. Instead of
downregulating DC development, treatment of GTS cultures with
antibodies to TNF (anti-TNF) on day 3 provoked the selective expansion
of the CD14-dependent (monocyte) DC pathway from progenitor cell
populations lacking CD14 and CD1a. After an initial decrease in
proliferation, anti-TNF produced a rebound in cell growth that yielded
intermediate myeloid progenitors exhibiting CD14-dependent DC
differentiation potential and CD14+CD1a+ DC
precursors. Cultures enriched in CD14-dependent DCs were more potent
stimulators of a mixed leukocyte reaction, compared with control
GTS cultures containing both types of DCs. The intermediate progenitors
expanded in the presence of anti-TNF were
CD115+CD33+DR+, long-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 function was acquired only when DC maturation was induced from these
myelodendritic progenitors with GM-CSF + interleukin-4 or GTS. These studies show a novel mechanism by which TNF regulates the DC
system, as well as providing a strategy for the amplification of the
CD14-dependent DC pathway from immature progenitors. Although TNF is
required to ensure the institution of DC hematopoiesis from
CD34+ progenitor cells, its activity on a later
progenitor appears to limit the development of CD14-dependent DCs.
© 1998 by The American Society of Hematology.
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