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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3647-3657
Flt3 Ligand Promotes the Generation of a Distinct CD34+
Human Natural Killer Cell Progenitor That Responds to Interleukin-15
Haixin Yu,
Todd A. Fehniger,
Pascal Fuchshuber,
Karl S. Thiel,
Eric Vivier,
William E. Carson, and
Michael A. Caligiuri
From the Divisions of Human Cancer Genetics, Hematology/Oncology, and
Surgical Oncology, Department of Pathology, and the Comprehensive
Cancer Center of The Ohio State University, Columbus, OH; the Division
of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY; and
the Centre d'Immunologie Institut National de la Santé et de la
Recherche Médicale/Centre National de la Recherche Scientifique
de Marseille-Luminy, Institut Universitaire de France,
Marseille, France.
Interleukin-15 (IL-15) is produced by human bone marrow (BM) stromal
cells and can induce CD34+ hematopoietic progenitor cells
(HPCs) to differentiate into CD56+CD3
natural killer (NK) cells in the absence of stromal cells. IL-15 mediates its effects by signaling through the  and  c
chains of the IL-2/15 receptor (R). The c-kit ligand (KL), also
produced by stromal cells, enhances the expansion of NK cells from
CD34+ HPCs in the presence of IL-15, but alone has no
ability to differentiate NK cells. Mice deficient in KL do not appear
to have a quantitative deficiency in NK cells, suggesting that other
stromal cell factors may contribute to NK cell expansion. Flt3 ligand
(FL) is also produced by BM stromal cells and has homology with KL.
Furthermore, mice with a targeted disruption of the FL gene have
reduced numbers of NK cells. We evaluated here the effects of FL on
human NK cell development and expansion from CD34+ HPCs.
Like KL, FL significantly enhanced the expansion of NK cells from
CD34+ HPCs in the presence of IL-15, compared with IL-15
alone. However, FL alone had no effect on NK cell differentiation. We
therefore explored the mechanism by which FL promotes IL-15-mediated
NK cell development. FL was found to induce IL-2/15R (CD122)
expression on CD34bright HPCs. The CD34bright
CD122+ cell coexpressed CD38, but lacked expression of
CD7, CD56, NK cell receptors (NKRs), or cytotoxic activity in the
absence of IL-15. Using limiting dilution analysis in the presence of
IL-15 alone, we demonstrated that the FL-induced
CD34brightCD122+ HPCs had an NK cell
precursor frequency 20- to 60-fold higher than the
CD34dim/negCD122 HPCs and 65- to 235-fold
higher than fresh CD34+ HPCs. KL had similar effects as
FL, but induced a significantly lower percentage of
CD34brightCD122+ cells (P  .01).
Both FL and KL also increased IL-15R transcript in
CD34+ HPCs. Culture of CD34+ HPCs in FL or
KL, followed by culture in IL-15 alone, induced expression of both
C-type lectin and Ig-superfamily NKRs on CD56+ cells.
These data collectively support a role for FL in early human NK cell
development. FL or KL generate a unique CD34bright
CD122+CD38+ human NK cell intermediate from
CD34+ HPCs that lacks NK features yet is
IL-15-responsive. IL-15 is then required for the induction of CD56 and
NKRs, LGL morphology, cytotoxic activity, and the ability to produce
abundant cytokines and chemokines.
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