Rigulation of T cell activation by intro-cellular phosphatase calcineurin

我们研究了细胞内磷酸酶钙调磷酸酶的调控作用。钙调磷酸酶是钙-钙调素依赖性磷酸酶，已知是免疫抑制药物FK506和环孢素a的靶点，由a链和B链组成。我们从小鼠钙调磷酸酶中获得了显性阴性，并建立了转基因小鼠。我们利用Lck远端启动子制作转基因小鼠，目的是指导转基因突变体Lck分子在T淋巴细胞中的高表达。我们得到了三行不同的拷贝号。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谱没有显著改变，3)成熟T细胞对抗TCR单抗产生细胞因子的反应减少，表明钙调磷酸酶在成熟T细胞中活化T细胞的重要作用，3)TCR结扎时钙内流不受影响。从这些结果来看，钙调磷酸酶似乎是T细胞在TCR识别抗原时激活所必需的。

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.