Mechanism of NK cell dysfunction in C/EBP-γ deficient mice

我分析了天然免疫细胞（包括NK细胞和树突状细胞）分化和激活的分子机制。缺乏转录因子C/EBP-γ的突变小鼠由于未知的原因表现出新生儿死亡。因此，为了分析C/EBP-γ-缺陷免疫细胞，我们建立了骨髓嵌合小鼠，并通过新生儿脾细胞的转移对其进行了分析。在C/EBP-γ-/-嵌合体中，B细胞和T细胞的发育和功能正常，NK细胞数量也正常。然而，在缺乏C/EBP-γ的情况下，NK细胞的功能，如细胞毒活性和IFN-γ的产生严重受损。值得注意的是，脾脏NK细胞功能障碍，而肝脏NK细胞未见功能障碍。这些结果表明C/EBP-γ对脾NK细胞的功能至关重要。toll样受体（TLR）信号可以诱导树突状细胞（dc）成熟。胞质粒接头MyD88与tlr相关，对tlr诱导的细胞因子诱导至关重要。对myd88缺陷小鼠的分析显示myd88独立的NF-κB激活响应TLR4信号。myd88缺陷DC在LPS的作用下可以增强共刺激分子的表面表达和T细胞刺激活性，表明myd88非依赖性通路可导致DC成熟。有趣的是，myd88缺陷DC不通过TLR4信号通路成熟。综上所述，每个TLR家族成员可以激活不同的信号级联来发挥其生物学效应。

I have analyzed the molecular mechanism on differentiation and activation of innate immune cells including NK or dendritic cells.1. Mutant mice lacking a transcription factor, C/EBP-γ, exhibited neonatal death due to unknown reasons. Therefore, to analyze C/EBP-γ-deficient immune cells, bone marrow chimeric mice were established and analyzed through the transfer of neonatal splenocytes. In C/EBP-γ-/- chimera, development and function of B and T cells were normal and NK cell numbers were also normal. However, NK cell function such as cytotoxic activity and IFN-γ production was severely impaired in the absence of C/EBP-γ. Notably, NK cell dysfunction was observed in splenic, but not hepatic, NK cells. These results suggest that C/EBP-γ is essential for splenic NK cell function.2. Toll-like receptor (TLR) signaling can induce maturation of dendritic cells (DCs). A cytoplasmice adaptor, MyD88, associates with TLRs and essential for TLR-induced cytokine induction. Analysis of MyD88-deficient mice revealed the MyD88-independent NF-κB activation in response to TLR4 signaling. MyD88-deficient DCs could enhance surface expression of costimulatory molecules and T cell stimulatory activity in response to LPS, indicating that the MyD88-independent path way can lead to DC maturation, Interestingly, MyD88-deficient DCs did not mature through TLR4 signaling. Taken together, each TLR family member can activate different signaling cascades to exert its biological effects.