A NULL MUTATION IN THE PERFORIN GENE IMPAIRS CYTOLYTIC T-LYMPHOCYTE-MEDIATED AND NATURAL-KILLER CELL-MEDIATED CYTOTOXICITY
A NULL MUTATION IN THE PERFORIN GENE IMPAIRS CYTOLYTIC T-LYMPHOCYTE-MEDIATED AND NATURAL-KILLER CELL-MEDIATED CYTOTOXICITY
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DOI：
10.1073/pnas.91.24.11571
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发表时间：
1994-11-22
影响因子：
11.1
通讯作者：
TSCHOPP, J
中科院分区：
文献类型：
--
作者：
LOWIN, B;BEERMANN, F;TSCHOPP, J
淋巴细胞介导的细胞毒性被认为是由颗粒储存的穿孔素的极化分泌导致靶细胞溶解组成。尽管如此，穿孔素非依赖性途径被假定来解释显然无穿孔素的淋巴细胞的细胞溶解活性和在垂死的靶细胞中发现的DNA降解。为了评估穿孔素的作用，我们在胚胎干细胞中使用基因靶向来产生缺乏穿孔素的小鼠。破坏基因的纯合子小鼠没有穿孔素mRNA。老鼠是健康的。无穿孔素的溶细胞性T细胞的活化和颗粒酶A分泌未改变。然而，溶细胞性T细胞以及自然杀伤（NK）细胞的杀伤活性受损但未被消除。当分析3T3成纤维细胞靶的裂解和YAC-1 NK靶的凋亡细胞死亡时，约三分之一的杀伤活性保留。我们的结论是，穿孔素是一个重要的效应分子在T细胞和NK细胞介导的细胞溶解。然而，也存在替代的穿孔素非依赖性溶解机制。
Lymphocyte-mediated cytotoxicity has beers proposed to consist of the polarized secretion of granule-stored perforin leading to target-cell lysis. Nevertheless, perforin-independent pathways were postulated to explain the cytolytic activity of apparently perforin-free lymphocytes and the DNA, degradation found in dying target cells. To evaluate the role of perforin, we used gene targeting in embryonic stem cells to produce mice lacking perforin. Mice homozygous for the disrupted gene have no perforin mRNA. The mice are healthy. Activation and granzyme A secretion of perforin free cytolytic T cells are unaltered. The killing activity of cytolytic T cells as well as natural killer (NK) cells, however, is impaired but not abolished. Approximately one third of the killing activity re mains when lysis of 3T3 fibroblast targets and the apoptotic cell death of YAC-1 NK targets are analyzed. We conclude that perforin is a crucial effector molecule in T cell- and NK cell-mediated cytolysis. However, alternative perforin-independent lytic mechanisms also exist.