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
Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9759-64. doi: 10.1073/pnas.1005186107. Epub 2010 May 10.
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.
一种名为warmflash（wmfl）的隐性N-乙基-N-亚硝基脲诱导突变揭示了病毒感染期间树突状细胞（DC）介导的自然杀伤（NK）细胞激活所必需的一种先前未被认识的信号。Wmfl纯合子对小鼠巨细胞病毒（MCMV）感染的易感性增加。在体内对MCMV感染的反应中，观察到NK细胞激活延迟，但未发现NK细胞激活或功能存在内在缺陷。相反，共培养实验表明，wmfl DC对NK细胞的激活效果欠佳，wmfl DC在对MCMV或合成TLR7和TLR9配体的反应中细胞因子产生受损。wmfl突变在编码Fms样酪氨酸激酶3（Flt3）的基因中被发现。Flt3配体（Flt3L）在感染或TLR激活后在血清中短暂诱导产生。然而，抗体阻断显示对Flt3L没有急性需求，这表明Flt3L→Flt3轴调控DC的发育，使其有能力支持NK效应功能。在缺乏Flt3信号的情况下，NK细胞激活延迟，并且在MCMV感染期间的存活明显受损。
