Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)9759-9764
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number21
DOIs
StatePublished - May 25 2010

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fms-Like Tyrosine Kinase 3
Muromegalovirus
Natural Killer Cells
Dendritic Cells
Cytomegalovirus Infections
Infection
Ethylnitrosourea
Mutation
Program Development
Homozygote
Virus Diseases
Coculture Techniques
Cytokines
Ligands
Antibodies
Serum
Genes
flt3 ligand protein

Keywords

  • Dendritic cell activation
  • Fms-like tyrosine kinase 3
  • Natural killer cell activation
  • Natural killer-dendritic cell crosstalk
  • Viral infection

ASJC Scopus subject areas

  • General

Cite this

Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells. / Eidenschenk, Céline; Crozat, Karine; Krebs, Philippe; Arens, Ramon; Popkin, Daniel; Arnold, Carrie N.; Blasius, Amanda L.; Benedict, Chris A.; Moresco, Eva Marie Y; Xia, Yu; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 21, 25.05.2010, p. 9759-9764.

Research output: Contribution to journalArticle

Eidenschenk, C, Crozat, K, Krebs, P, Arens, R, Popkin, D, Arnold, CN, Blasius, AL, Benedict, CA, Moresco, EMY, Xia, Y & Beutler, B 2010, 'Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 21, pp. 9759-9764. https://doi.org/10.1073/pnas.1005186107
Eidenschenk, Céline ; Crozat, Karine ; Krebs, Philippe ; Arens, Ramon ; Popkin, Daniel ; Arnold, Carrie N. ; Blasius, Amanda L. ; Benedict, Chris A. ; Moresco, Eva Marie Y ; Xia, Yu ; Beutler, Bruce. / Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 21. pp. 9759-9764.
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