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 language | English (US) |
|---|---|
| Pages (from-to) | 9759-9764 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 107 |
| Issue number | 21 |
| DOIs | |
| State | Published - May 25 2010 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells
AU - Eidenschenk, Céline
AU - Crozat, Karine
AU - Krebs, Philippe
AU - Arens, Ramon
AU - Popkin, Daniel
AU - Arnold, Carrie N.
AU - Blasius, Amanda L.
AU - Benedict, Chris A.
AU - Moresco, Eva Marie Y
AU - Xia, Yu
AU - Beutler, Bruce
PY - 2010/5/25
Y1 - 2010/5/25
N2 - 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.
AB - 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.
KW - Dendritic cell activation
KW - Fms-like tyrosine kinase 3
KW - Natural killer cell activation
KW - Natural killer-dendritic cell crosstalk
KW - Viral infection
UR - http://www.scopus.com/inward/record.url?scp=77953116827&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77953116827&partnerID=8YFLogxK
U2 - 10.1073/pnas.1005186107
DO - 10.1073/pnas.1005186107
M3 - Article
VL - 107
SP - 9759
EP - 9764
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 21
ER -