Altered compensatory cytokine signaling underlies the discrepancy between Flt3 and Flt3l mice

The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe in Flt3l mice than in Flt3 mice. This has led to speculation that Flt3L binds to another receptor that also supports DC development. However, we found that Flt3L administration does not generate DCs in Flt3 mice, arguing against a second receptor. Instead, Flt3 DC progenitors matured in response to macrophage colony-stimulating factor (M-CSF) or stem cell factor, and deletion of Csf1r in Flt3 mice further reduced DC development, indicating that these cytokines could compensate for Flt3. Surprisingly, Flt3 DC progenitors displayed enhanced M-CSF signaling, suggesting that loss of Flt3 increased responsiveness to other cytokines. In agreement, deletion of Flt3 in Flt3l mice paradoxically rescued their severe DC deficiency. Thus, multiple cytokines can support DC development, and the discrepancy between Flt3 and Flt3l mice results from the increased sensitivity of Flt3 progenitors to these cytokines.