Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo.
Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and dendritic cells (DCs) in humans and mice. The exact developmental stages at which hematopoietic progenitors express Flt3, are responsive to its ligand, and subsequently develop to DCs, are not known. Here we show that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3. The receptor is down-regulated once definitive B cell, T cell, and megakaryocyte/erythrocyte commitment occurs, and Flt3 is not detectable on other steady state hematopoietic cell populations. Upon in vivo Flt3 ligand (Flt3L) administration, Flt3+ progenitor cells and their progeny DCs are expanded, whereas Flt3- downstream progenitors are not, or are only slightly increased. Transplantation of common lymphoid and common myeloid progenitors and subsequent Flt3L injection increases progeny DCs of both precursor populations. These findings provide a definitive map of Flt3 expression in the hematopoietic hierarchy and directly demonstrate that Flt3L can drive DC development along both the lymphoid and myeloid developmental pathways from Flt3+ progenitors to Flt3+ DCs.
Karsunky
Holger
H
Institute for Research in Biomedicine (IRB), Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland. karunsky@stanford.edu
Merad
Miriam
M
Cozzio
Antonio
A
Weissman
Irving L
IL
Manz
Markus G
MG
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology*; D012867:Skin / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D051941:fms-Like Tyrosine Kinase 3
D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C084881:flt3 ligand protein; C497971:Flt3 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3