Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon–producing and dendritic cell development

Flt3 ligand (Flt3L) is a nonredundant cytokine in type I interferon–producing cell (IPC) and dendritic cell (DC) development, and IPC and DC differentiation potential is confined to Flt3⁺ hematopoietic progenitor cells. Here, we show that overexpression of human Flt3 in Flt3⁻ (Flt3⁻Lin⁻IL-7Rα⁻Thy1.1⁻c-Kit⁺) and Flt3⁺ (Flt3⁺Lin⁻IL-7Rα⁻Thy1.1⁻c-Kit⁺) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. In defined hematopoietic cell populations, such as Flt3⁻ megakaryocyte/erythrocyte-restricted progenitors (MEPs), enforced Flt3 signaling induces transcription of IPC, DC, and granulocyte/macrophage (GM) development–affiliated genes, including STAT3, PU.1, and G-/M-/GM-CSFR, and activates differentiation capacities to these lineages. Moreover, ectopic expression of Flt3 downstream transcription factors STAT3 or PU.1 in Flt3⁻ MEPs evokes Flt3 receptor expression and instructs differentiation into IPCs, DCs, and myelomonocytic cells, whereas GATA-1 expression and consecutive megakaryocyte/erythrocyte development is suppressed. Based on these data, we propose a demand-regulated, cytokine-driven DC and IPC regeneration model, in which high Flt3L levels initiate a self-sustaining, Flt3-STAT3– and Flt3-PU.1–mediated IPC and DC differentiation program in Flt3⁺ hematopoietic progenitor cells.