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.

我已经分析了包括NK或树突细胞在内的先天免疫细胞分化和激活的分子机制。1。由于未知原因，缺乏转录因子C/EBP-γ的突变小鼠暴露于新生儿死亡。因此，为了分析C/EBP-γ缺乏免疫细胞，建立了骨髓嵌合小鼠，并通过新生儿脾细胞的转移来分析。在C/EBP-γ - / - 嵌合体中，B和T细胞的发育和功能正常，NK细胞数也正常。但是，在没有C/EBP-γ的情况下，NK细胞功能（例如细胞毒性活性和IFN-γ的产生）严重受损。值得注意的是，在脾脏，但未观察到NK细胞功能障碍。这些结果表明C/EBP-γ对于脾NK细胞功能至关重要。2。 Toll样受体（TLR）信号传导可诱导树突状细胞（DCS）的成熟。 MyD88的细胞质适配器与TLR相关，对于TLR诱导的细胞因子诱导至关重要。对MyD88缺陷小鼠的分析揭示了对TLR4信号的响应，非依赖MyD88的NF-κB激活。 MyD88缺陷DC可以增强对LP的反应的共刺激分子和T细胞刺激活性的表面表达，这表明MyD88独立的途径可以导致DC成熟，有趣的是，MyD88缺陷型DC并未通过TLR4信号传递成熟。综上所述，每个TLR家族成员都可以激活不同的信号级联以执行其生物学作用。