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 Blood, 15 October 2007, Vol. 110, No. 8, pp. 2955-2964.
Prepublished online as a Blood First Edition Paper on May 31, 2007; DOI 10.1182/blood-2006-10-054726.

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IMMUNOBIOLOGY

Critical role of FLT3 ligand in IL-7 receptor–independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors

Ewa Sitnicka1, Natalija Buza-Vidas1, Henrik Ahlenius1, Corrado M. Cilio2, Christos Gekas1, Jens M. Nygren1, Robert Månsson1, Min Cheng1, Christina T. Jensen1, Marcus Svensson3, Karin Leandersson4, William W. Agace3, Mikael Sigvardsson1, and Sten Eirik W. Jacobsen1

1 Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund; 2 Department of Clinical Sciences and Department of Paediatrics, Cellular Autoimmunity Unit, Malmö University Hospital, Malmö; 3 Immunology Section, Department of Cell and Molecular Biology, Lund University, Lund; 4 Experimental Pathology, Malmö University Hospital, Malmö, Sweden

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-7R{alpha}) 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-7R{alpha}–independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7R{alpha}, in regulation of the earliest lineage-negative (Lin–) Lin–SCA1+KIT+ (LSK) FLT3hi lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.


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