Functional analysis of the non-HLA genes within major histocompatibility complex (MHC) region with the use of gene-targeted mice

使用基因靶向小鼠对主要组织相容性复合体 (MHC) 区域内的非 HLA 基因进行功能分析

• 批准号: 13670320
• 负责人: MATSUMITO Mitsuru
• 金额: $ 2.3万
• 依托单位: University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670320/
• 关键词: Lymphotoxin receptor; Signal transduction; NF-Kb; NIK; T cell; リンホトキシン; TNFレセプター; ノックアウトマウス

NF-Kb-inducting kinase (NIK) is involved in lymphoid organogenesis in mice through lymphotoxin-b receptor signaling. To clarify the roles of NIK in T cell activation through TCR/CD3 and co atimulation pahways, we have studied the function of T cells from aly mice, a strain with mutant NIK. NIK mutant T cells showed impaired proliferation and IL-2 production in respones to anti-CD3 stim ulation, and these effects were caused by impaired NF-Kb activity in both mature and immature T cells; the impaired NF-Kb. In contrast, responses to co- stimulatory signals were largely retained in aly mice, suggesting that NIK is not uniquely coupled to the co-stim ulatory pathways. When NIK mutant T cells were stimulated in the presence of a protein kinase C (PKC) inhibitor, proliferative responses were abrogated more severely than in control mice, suggesting that both NIK and PKC control T cell activation in a cooperative manner. We also demonstrated that NIK and PKC are involved in distinct NF-Kb activation pathways downstream of TCR/CD3. These results suggest critical roles for NIK in setting the threshold for T cell activation, and partly account for the immunodeficiency in aly mice.

NF-Kb诱导激酶（NIK）通过淋巴毒素b受体信号传导参与小鼠淋巴器官发生。为了阐明NIK通过TCR/CD 3途径和共刺激途径在T细胞活化中的作用，我们研究了突变型NIK小鼠T细胞的功能。NIK突变型T细胞显示出对抗CD 3刺激应答的增殖和IL-2产生受损，并且这些效应是由成熟和未成熟T细胞中受损的NF-Kb活性引起的;受损的NF-Kb。相比之下，对共刺激信号的反应在很大程度上保留在aly小鼠中，表明NIK不是唯一偶联至共刺激通路的。当NIK突变T细胞刺激蛋白激酶C（PKC）抑制剂的存在下，增殖反应被废除更严重的比对照小鼠，这表明NIK和PKC控制T细胞活化的合作方式。我们还证明了NIK和PKC参与TCR/CD 3下游不同的NF-Kb活化途径。这些结果表明NIK在设定T细胞活化阈值中起关键作用，并部分解释了aly小鼠的免疫缺陷。

项目成果

Matsushima,A, et al.: "Essential role of NF-Kb-inducing kinase and IkB-kinase a in NF-Kb activation through lymphotoxin-B receptor, but not through TNF receptor-I"Journal of Experimental Medicine. 193. 631-636 (2001)

Matsushima,A 等人：“NF-Kb 诱导激酶和 IkB 激酶 a 在通过淋巴毒素 B 受体而非 TNF 受体 I 激活 NF-Kb 中的重要作用”《实验医学杂志》。

Matsumoto, M., et al.: "Essential role of NF-κB-inducing kinase in T cell activation through the TCR/CD3 pathway"Journal of Immunology. 169. 1151-1158 (2002)

Matsumoto, M., et al.：“NF-κB 诱导激酶通过 TCR/CD3 途径激活 T 细胞的重要作用”免疫学杂志 169. 1151-1158 (2002)。

Matsumoto,M, et al.: "Essential role of NF-Kb-inducing kinase in T cell activation through the TCR/CD3 pathway"Journal of Immunology. 169. 1151-1158 (2002)

Matsumoto,M 等人：“NF-Kb 诱导激酶通过 TCR/CD3 途径激活 T 细胞的重要作用”免疫学杂志。

Matsushima, A., et al.: "Essential role of NF-κB-inducing kinase and IκB-kinase α in NF-κB activation through lymphotoxin-β receptor, but not through TNF receptor-I"Journal of Experimental Medicine. 193. 631-636 (2001)

Matsushima, A. 等人：“NF-κB 诱导激酶和 IκB 激酶 α 在通过淋巴毒素-β 受体而非 TNF 受体-I 激活 NF-κB 中的重要作用”《实验医学杂志》193。 631-636 (2001)

Matsushima, A., et al.: "Essential role of NF-κB-inducing kinase and IκB-kinase αin NF-κB activation through lymphotoxin-β receptor, but not through TNF receptor-I"Journal of Experimemtal Medicine. 193(5). 631-636 (2001)

Matsushima, A. 等人：“NF-κB 诱导激酶和 IκB 激酶 α 在通过淋巴毒素-β 受体而非 TNF 受体-I 激活 NF-κB 中的重要作用”实验医学杂志 193(5)。 ））。631-636（2001）