Abstract |
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.
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Authors | Céline Eidenschenk, Karine Crozat, Philippe Krebs, Ramon Arens, Daniel Popkin, Carrie N Arnold, Amanda L Blasius, Chris A Benedict, Eva Marie Y Moresco, Yu Xia, Bruce Beutler |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 107
Issue 21
Pg. 9759-64
(May 25 2010)
ISSN: 1091-6490 [Electronic] United States |
PMID | 20457904
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Flt3 protein, mouse
- fms-Like Tyrosine Kinase 3
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Topics |
- Animals
- Cell Survival
- Cells, Cultured
- Dendritic Cells
(immunology)
- Herpesviridae Infections
(immunology)
- Killer Cells, Natural
(cytology, immunology)
- Lymphocyte Activation
- Mice
- Muromegalovirus
(immunology)
- Mutation
- Signal Transduction
- fms-Like Tyrosine Kinase 3
(genetics, immunology)
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