Consistent Activation of Flt3 Promotes Hematopoietic Progenitors Toward Dendritic Cell Development in Mouse

Abstract 4789

Dendritic cells (DCs) play key roles in mediating innate and acquired immune responses. DCs have a short half life in peripheral organs and are derived constitutively from bone marrow hematopoietic stem cells (HSCs) and Flt3⁺ progenitors. Cytokine signaling from Flt3 is crucial for stimulation of DC development. Previous studies demonstrated that injection of Flt3 ligand (Flt3L) in mouse caused a transient, but substantial increase in DC development. The effects of long-term activation of Flt3 signaling with physiological levels of Flt3L, however, have not yet been defined. Transgenic mice with constitutively activated Flt3 signaling were generated by replacing the Flt3 alleles with a mutant version Flt3ITD. Both mature DCs and DC progenitors increased modestly in Flt3ITD mice; both lymphoid and myeloid derived DCs were increased compared with wild type mice. Although the level of DCs in Flt3ITD mice did not reach the high levels in mice injected with Flt3L, the effect of Flt3ITD on DC development was consistent and long-lasting. Thus, activation of Flt3 signaling by different mechanisms led to distinct responses of bone marrow stem and progenitor cells for DC development. Flt3ITD mice provide a unique model to analyze DC differentiation from bone marrow stem and progenitor cells at physiological levels of Flt3L.