Pardo Julián, Balkow Sandra, Anel Alberto, Simon Markus M
Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain.
Eur J Immunol. 2002 Oct;32(10):2881-7. doi: 10.1002/1521-4141(2002010)32:10<2881::AID-IMMU2881>3.0.CO;2-K.
Studies with perforin-deficient mice firmly established perforin as a key element in cytotoxic T cell (CTL) / natural killer (NK) cell-mediated tumor control but did not reveal the role of granzyme (gzm) A and B. A contribution of gzm in these processes was indicated by earlier in vitro experiments employing purified effector molecules demonstrated that tumor cell apoptosis and death only occurred in the presence of both, perf and gzm. However, recent work using mice deficient in either gzmA, gzmB or both gzm suggested that only perf but neither of the two gzm are critical for tumor surveillance by CTL or NK cells. In light of the conflicting results we have re-investigated this issue by analyzing the potential of mice deficient in one or more component(s) of the exocytosis pathway to control NK-sensitive syngeneic MHC class I-defective RMA-S tumor cells in vivo. Our results show that in contrast to wild-type mice, mice deficient for both gzm exhibit an uncontrolled tumor growth with a time kinetic similar to that of perforin-deficient mice. Together with the finding that a defect of mice in either gzmA or gzmB alone also leads to an increased susceptibility to tumor growth, at least to a certain extent when compared to wild-type mice, the data clearly indicate that a concerted action of perforin and the two gzm is mandatory for optimal NK cell-mediated tumor control in vivo. Most notably, the in vivo potential of the respective NK cell populations was only reflected by their nucleolytic, but not their cytolytic activities in vitro.
对穿孔素缺陷小鼠的研究明确证实穿孔素是细胞毒性T细胞（CTL）/自然杀伤（NK）细胞介导的肿瘤控制中的关键要素，但未揭示颗粒酶（gzm）A和B的作用。早期使用纯化效应分子的体外实验表明，在这些过程中gzm有一定作用，该实验证明肿瘤细胞凋亡和死亡仅在穿孔素和gzm同时存在时才会发生。然而，最近使用gzmA缺陷、gzmB缺陷或两者均缺陷的小鼠进行的研究表明，对于CTL或NK细胞的肿瘤监测而言，只有穿孔素是关键的，而这两种gzm都不是关键的。鉴于这些相互矛盾的结果，我们通过分析体内缺乏胞吐途径中一种或多种成分的小鼠控制NK敏感的同基因MHC I类缺陷RMA-S肿瘤细胞的潜力，重新研究了这个问题。我们的结果表明，与野生型小鼠相比，两种gzm均缺陷的小鼠肿瘤生长不受控制，其时间动态与穿孔素缺陷小鼠相似。此外还发现，单独gzmA或gzmB缺陷的小鼠也会导致对肿瘤生长的易感性增加，至少与野生型小鼠相比在一定程度上如此，这些数据清楚地表明，穿孔素和两种gzm的协同作用对于体内最佳的NK细胞介导的肿瘤控制是必不可少的。最值得注意的是，各个NK细胞群体的体内潜力仅通过其体外核酸分解活性而非细胞溶解活性来反映。
