TY - JOUR
T1 - Altered compensatory cytokine signaling underlies the discrepancy between Flt3-/- and Flt3l-/- mice
AU - Durai, Vivek
AU - Bagadia, Prachi
AU - Briseño, Carlos G.
AU - Theisen, Derek J.
AU - Iwata, Arifumi
AU - Davidson, Jesse T.
AU - Gargaro, Marco
AU - Fremont, Daved H.
AU - Murphy, Theresa L.
AU - Murphy, Kenneth M.
N1 - Funding Information:
We thank Dr. E. Camilla Forsberg for Flt3-/- mice and the AlvinJ. Siteman Cancer Center at Washington University School ofMedicine for use of the Center for Biomedical Informatics and Multiplex Gene Analysis Genechip Core Facility. We thank AnsumanT. Satpathy and Xiaodi Wu for their helpful suggestionson this manuscript. We thank Hannah L. Miller for technicalhelp with pDC assays.This work was supported by the Howard Hughes MedicalInstitute (K.M. Murphy), the US National Institutes of Health (grant F30DK108498 to V. Durai, grant T32 AI007163-40 to D.J.Theisen, and grant T32 CA 009621 to J.T. Davidson IV), and the US National Science Foundation (grant DGE-1143954 to P. Bagadia).The authors declare no competing financial interests.Author contributions: V. Durai, T.L. Murphy, and K.M. Murphydesigned the study with advice from D.H. Fremont; V. Duraiand P. Bagadia performed experiments related to cell sorting, cellculture, and flow cytometry with advice from C.G. Briseño and J.T.Davidson IV; V. Durai, C.G. Briseño, and M. Gargaro performed invivo manipulations of mice with advice from A. Iwata; V. Duraiand D.J. Theisen performed cross-presentation assays; V. Durai,T.L. Murphy, and K.M. Murphy wrote the manuscript with contributionsfrom all authors.
Funding Information:
This work was supported by the Howard Hughes Medical Institute (K.M. Murphy), the US National Institutes of Health (grant F30DK108498 to V. Durai, grant T32 AI007163-40 to D.J. Theisen, and grant T32 CA 009621 to J.T. Davidson IV), and the US National Science Foundation (grant DGE-1143954 to P. Bagadia). The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Durai et al.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85046754948&partnerID=8YFLogxK
U2 - 10.1084/jem.20171784
DO - 10.1084/jem.20171784
M3 - Article
C2 - 29572360
AN - SCOPUS:85046754948
SN - 0022-1007
VL - 215
SP - 1417
EP - 1435
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
ER -