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

• 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

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.

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原因表现出新生儿死亡。因此，为了分析C/EBP-γ缺陷型免疫细胞，建立了骨髓嵌合小鼠，并通过新生脾细胞的转移进行分析。在C/EBP-γ-/-嵌合体中，B和T细胞的发育和功能正常，NK细胞数量也正常。然而，NK细胞的功能，如细胞毒活性和IFN-γ的产生严重受损，在C/EBP-γ的情况下。值得注意的是，在脾NK细胞中观察到NK细胞功能障碍，但在肝NK细胞中未观察到。这些结果提示C/EBP-γ对脾NK细胞功能是必需的. Toll样受体（TLR）信号可以诱导树突状细胞（DC）成熟。MyD 88是一种与TLR相关的细胞质适配器，对TLR诱导的细胞因子诱导至关重要。对MyD 88缺陷小鼠的分析揭示了响应于TLR 4信号传导的MyD 88非依赖性NF-κB活化。MyD 88缺陷的DC可增强LPS刺激下DC表面共刺激分子的表达和T细胞刺激活性，提示MyD 88非依赖性途径可导致DC成熟。有趣的是，MyD 88缺陷的DC不通过TLR 4信号途径成熟。总之，每个TLR家族成员可以激活不同的信号级联以发挥其生物学效应。

项目成果

T.Kaisho, et al.: "Toll-like receptors and their signaling mechanism in innate immunity"Acta Odontologica Scandinavica. 59. 124-130 (2001)

T.Kaisho 等人：“Toll 样受体及其在先天免疫中的信号传导机制”Acta Odontologica Scandinavica。

T.Kaisho, et al.: "Endotoxin-induced maturation of My D88-deficient dendritic cells"J. Immunol.. 166. 5688-5694 (2001)

T.Kaisho 等人：“内毒素诱导的 My D88 缺陷树突状细胞的成熟”J.

H. Hemmi, et al.: "A novel Toll-like receptor that recognizes bacterial DNA."Nature. 408. 740-745 (2000)

H. Hemmi 等人：“一种识别细菌 DNA 的新型 Toll 样受体。”《自然》。

T.Kaishi, et al.: "Critical roles of Toll-like receptors in host defense."Critical Reviews in Immunology.. 20・5. 393-405 (2000)

T. Kaishi 等人：“Toll 样受体在宿主防御中的关键作用。”免疫学批判评论.. 20・5（2000）。

S. Akira, et al.: "Toll-like receptors : critical proteins linking innate and acquired immunity"Nat Immunol. 2. 675-680 (2001)

S. Akira 等人：“Toll 样受体：连接先天性和后天性免疫的关键蛋白质”NatImmunol。