Altered compensatory cytokine signaling underlies the discrepancy between <i>Flt3–/–</i> and <i>Flt3l–/–</i> mice

Abstract

The receptor Flt3 and its ligand Flt3L are both critical for dendritic cell (DC) development, but DC deficiency is more severe in <i>Flt3l^-/-</i> mice than in <i>Flt3^-/-</i> 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 <i>Flt3^-/-</i> mice, arguing against a second receptor. Instead, <i>Flt3^-/-</i> DC progenitors matured in response to macrophage colony-stimulating factor (M-CSF) or stem cell factor, and deletion of <i>Csf1r</i> in <i>Flt3^-/-</i> mice further reduced DC development, indicating that these cytokines could compensate for Flt3. Surprisingly, <i>Flt3^-/-</i> DC progenitors displayed enhanced M-CSF signaling, suggesting that loss of Flt3 increased responsiveness to other cytokines. In agreement, deletion of Flt3 in <i>Flt3l^-/-</i> mice paradoxically rescued their severe DC deficiency. Thus, multiple cytokines can support DC development, and the discrepancy between <i>Flt3^-/-</i> and <i>Flt3l^-/-</i> mice results from the increased sensitivity of <i>Flt3^-/-</i> progenitors to these cytokines.