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

Abstract

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 α (IL-7Rα) 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-7Rα–independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Rα, 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.