Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells.
A previously unappreciated signal necessary for dendritic cell (DC)-mediated activation of natural killer (NK) cells during viral infection was revealed by a recessive N-ethyl-N-nitrosourea-induced mutation called warmflash (wmfl). Wmfl homozygotes displayed increased susceptibility to mouse cytomegalovirus (MCMV) infection. In response to MCMV infection in vivo, delayed NK cell activation was observed, but no intrinsic defects in NK cell activation or function were identified. Rather, coculture experiments demonstrated that NK cells are suboptimally activated by wmfl DCs, which showed impaired cytokine production in response to MCMV or synthetic TLR7 and TLR9 ligands. The wmfl mutation was identified in the gene encoding the Fms-like tyrosine kinase 3 (Flt3). Flt3 ligand (Flt3L) is transiently induced in the serum upon infection or TLR activation. However, antibody blockade reveals no acute requirement for Flt3L, suggesting that the Flt3L --> Flt3 axis programs the development of DCs, making them competent to support NK effector function. In the absence of Flt3 signaling, NK cell activation is delayed and survival during MCMV infection is markedly compromised.
Eidenschenk
Céline
C
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Crozat
Karine
K
Krebs
Philippe
P
Arens
Ramon
R
Popkin
Daniel
D
Arnold
Carrie N
CN
Blasius
Amanda L
AL
Benedict
Chris A
CA
Moresco
Eva Marie Y
EM
Xia
Yu
Y
Beutler
Bruce
B
D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006566:Herpesviridae Infections / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D018146:Muromegalovirus / Q000276:immunology*; D009154:Mutation; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000276:immunology*
C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3
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