Rigulation of T cell activation by intro-cellular phosphatase calcineurin

细胞内磷酸酶钙调神经磷酸酶对 T 细胞活化的调节

• 批准号: 08839021
• 负责人: NAKAYAMA Toshinori
• 金额: $ 1.15万
• 依托单位: Science University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08839021/
• 关键词: Calcineurin; Tcell activation; Transgenic; dominant-negative; ドミナントネガティブ; T細胞; トランスジェニックマウス; トシナント ネビティブ

We studied regulatory roles of intra-cellular phosphatase, calcineurin. Calcineurin is calcium-calmodulin-dependent phosphatase, and known to be a target of immunosuppressive drug, FK506 and Cyclosporin A.It consists of A and B chains.Here we generated a dominant-negative from of murine calcineurin, and established transgenic mice. We used lck-distal promoter for making transgenic mouse in order to direct high expression of transgenic mutant Lck molecules in T lymphocyte. We obtained three lines with different copy numbers. From analyzes with these mice, we found that 1) total cell number of thymocyte was decreased at 30-50%, 2) CD4/CD8 profiles were not significantly changed, 3) mature T cell response to produce cytokines against anti-TCR mAb was decreased, suggesting essential roles of calcineurin for T cell activation in mature T cells, and 3) calcium influx upon TCR ligation was not affected. From these results, calcineurin appeared to essntial for T cell activation upon antigen recognition by TCR.

我们研究了细胞内磷酸酶、钙调神经磷酸酶的调节作用。钙调神经磷酸酶是钙钙调蛋白依赖性磷酸酶，已知是免疫抑制药物 FK506 和环孢菌素 A 的靶点。它由 A 链和 B 链组成。在这里，我们从鼠类钙调神经磷酸酶中产生了显性失活，并建立了转基因小鼠。我们使用lck-远端启动子来制备转基因小鼠，以指导转基因突变体Lck分子在T淋巴细胞中高表达。我们获得了具有不同拷贝数的三行。通过对这些小鼠的分析，我们发现 1) 胸腺细胞总数减少了 30-50%，2) CD4/CD8 谱没有显着改变，3) 成熟 T 细胞产生针对抗 TCR mAb 的细胞因子的反应减少，表明钙调神经磷酸酶在成熟 T 细胞中对 T 细胞激活的重要作用，3) TCR 连接后的钙流入不受影响。从这些结果来看，钙调神经磷酸酶似乎对于 TCR 识别抗原后 T 细胞的激活至关重要。

项目成果

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Tada, T.：“自我耐受：T 细胞周围免疫反应的多种策略”，过敏新趋势 1・1 (1997)。

Kubo, M.: "T cell subset-specific expression of the IL-4 gene is regulated by a silencer element and STAT6" EMOO,J.16・7. 4009-4020 (1997)

Kubo, M.：“IL-4 基因的 T 细胞亚群特异性表达由沉默元件和 STAT6 调节” EMOO,J.16·7 (1997)。

Tada,T.: "Self Tolerance:Multiple strategies for poriphrical linrespon the lides of tuu" New Trends in Allorgy. 1.1. 369-364 (1997)

Tada,T.：“自我宽容：对 tuu 的 lides 进行 poriphrical linrespon 的多种策略”Allorgy 的新趋势。

Kubo,M.: "T cell subset-specific expression of the IL-4gene is iogulated by a silencer element and STAT6" EMBO-T. 16.7. 4007-4020 (1997)

Kubo,M.：“IL-4 基因的 T 细胞亚群特异性表达由沉默元件和 STAT6 调节”EMBO-T。

Hasegawa, A.: "Regulation of T cell autoreactivity to MHC class II by controlling CD80 expression on B cells" Int.Immunol. (印刷中). (1998)

Hasekawa, A.：“通过控制 B 细胞上的 CD80 表达来调节 T 细胞对 MHC II 类的自身反应”（Int.Immunol）。