期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 21, 页码 9759-9764出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1005186107
关键词
Fms-like tyrosine kinase 3; natural killer-dendritic cell crosstalk; viral infection; natural killer cell activation; dendritic cell activation
资金
- European Molecular Biology Organization
- Swiss National Science Foundation
- US National Institutes of Health [P01 AI070167-01]
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 themcompetent 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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