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

Vivek Durai, Prachi Bagadia, Carlos G. Briseño, Derek J. Theisen, Arifumi Iwata, Jesse T. Davidson, Marco Gargaro, Daved H. Fremont, Theresa L. Murphy, Kenneth M. Murphy

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1417-1435
Number of pages19
JournalJournal of Experimental Medicine
Volume215
Issue number5
DOIs
StatePublished - May 1 2018

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