Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells.
The ligand for the receptor tyrosine kinase fms-like tyrosine kinase 3 (flt3), also referred to as fetal liver kinase-2 (flk-2), has an important role in hematopoiesis. The flt3 ligand (flt3L) is a growth factor for hematopoietic progenitors and induces hematopoietic progenitor and stem cell mobilization in vivo. In addition, when mice are treated with flt3L immature B cells, natural killer (NK) cells and dendritic cells (DC) are expanded in vivo. To further elucidate the role of flt3L in hematopoiesis, mice lacking flt3L (flt3L-/-) were generated by targeted gene disruption. Leukocyte cellularity was reduced in the bone marrow, peripheral blood, lymph nodes (LN), and spleen. Thymic cellularity, blood hematocrit, and platelet numbers were not affected. Significantly reduced numbers of myeloid and B-lymphoid progenitors were noted in the BM of flt3L-/- mice. In addition a marked deficiency of NK cells in the spleen was noted. DC numbers were also reduced in the spleen, LN, and thymus. Both myeloid-related (CD11c(++) CD8alpha(-)) and lymphoid-related (CD11c(++) CD8alpha(+)) DC numbers were affected. We conclude that flt3L has an important role in the expansion of early hematopoietic progenitors and in the generation of mature peripheral leukocytes.
McKenna
H J
HJ
Immunex Corporation, Seattle, WA 98101, USA.
Stocking
K L
KL
Miller
R E
RE
Brasel
K
K
De Smedt
T
T
Maraskovsky
E
E
Maliszewski
C R
CR
Lynch
D H
DH
Smith
J
J
Pulendran
B
B
Roux
E R
ER
Teepe
M
M
Lyman
S D
SD
Peschon
J J
JJ
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D003114:Colony-Forming Units Assay; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D015698:Genomic Library; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D007700:Kinetics; D007962:Leukocytes / Q000166:cytology; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology
D015851:Interleukin-7; D008024:Ligands; D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D011070:Poly I-C