Critical role of FLT3 ligand in IL-7 receptor independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors.
The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)-deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor alpha (IL-7Ralpha) signaling. Fl-/-Il-7r-/- mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Ralpha-independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Ralpha, in regulation of the earliest lineage-negative (Lin(-)) Lin(-)SCA1+KIT+ (LSK) FLT3(hi) lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
Sitnicka
Ewa
E
Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
Buza-Vidas
Natalija
N
Ahlenius
Henrik
H
Cilio
Corrado M
CM
Gekas
Christos
C
Nygren
Jens M
JM
Månsson
Robert
R
Cheng
Min
M
Jensen
Christina T
CT
Svensson
Marcus
M
Leandersson
Karin
K
Agace
William W
WW
Sigvardsson
Mikael
M
Jacobsen
Sten Eirik W
SE
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D005333:Fetus; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D007091:Image Processing, Computer-Assisted; D038041:Lymphopoiesis / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology / Q000473:pathology
D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D020395:Receptors, Interleukin-7; C084881:flt3 ligand protein