Altered compensatory cytokine signaling underlies the discrepancy between and mice.

The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe in mice than in 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 mice, arguing against a second receptor. Instead, DC progenitors matured in response to macrophage colony-stimulating factor (M-CSF) or stem cell factor, and deletion of Csf1r in mice further reduced DC development, indicating that these cytokines could compensate for Flt3. Surprisingly, DC progenitors displayed enhanced M-CSF signaling, suggesting that loss of Flt3 increased responsiveness to other cytokines. In agreement, deletion of Flt3 in mice paradoxically rescued their severe DC deficiency. Thus, multiple cytokines can support DC development, and the discrepancy between and mice results from the increased sensitivity of progenitors to these cytokines.

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