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

C/EBP-γ缺陷小鼠NK细胞功能障碍的机制

基本信息

批准号：
12670304
负责人：
KAISHO Tsuneyasu
金额：
$ 2.18万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670304/
关键词：
Gene targeting innate immunity adaptive immunity NK cell Dendritic cell LPS

项目摘要

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.

我分析了包括NK或树突状细胞在内的先天免疫细胞分化和激活的分子机制。 1．缺乏转录因子C/EBP-γ的突变小鼠，表现出不明原因的新生死亡。因此，对C/EBP进行分析。通过新生脾细胞移植建立γ-缺陷免疫细胞骨髓嵌合小鼠并进行分析。在C/EBP-γ-/-嵌合体中，B细胞和T细胞发育和功能正常，NK细胞数量正常。然而，在缺乏 C/EBP-γ 的情况下，NK 细胞功能（例如细胞毒性活性和 IFN-γ 产生）严重受损。值得注意的是，在脾脏 NK 细胞中观察到 NK 细胞功能障碍，但在肝脏中却没有。 C/EBP-γ 对于脾 NK 细胞功能至关重要。2. Toll 样受体 (TLR) 信号传导可以诱导树突状细胞 (DC) 的成熟。 MyD88 与 TLR 相关，对 TLR 诱导的细胞因子诱导至关重要。对 MyD88 缺陷小鼠的分析表明，MyD88 缺陷型 DC 中不依赖 MyD88 的 NF-κB 激活可以增强共刺激分子和 T 细胞刺激的表面表达。响应 LPS 的活性，表明 MyD88 独立途径可导致 DC 成熟，提示 MyD88 缺陷的 DC 未成熟通过TLR4信号传导，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。