Lee R K, Spielman J, Zhao D Y, Olsen K J, Podack E R
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33136, USA.
J Immunol. 1996 Sep 1;157(5):1919-25.
Lymphokine-activated killer (LAK) cells generated from perforin knockout mice possess significantly reduced cytotoxicity against a panel of tumor target cell lines, with some tumor cells being lysed exclusively by the perforin pathway. LAK cells are also capable of Fas ligand-mediated cytotoxicity. LAK cells generated from mice deficient in both perforin and Fas ligand (PKO/gld) were not cytolytic in short term cytotoxicity assays, demonstrating that perforin and Fas ligand are required for acute target cell lysis. However, PKO/gld LAK cells were cytotoxic in long term cytotoxicity assays against TNF-sensitive tumor lines, and this cytotoxicity was completely inhibited by neutralizing TNF Abs. This potent TNF cytotoxicity has not been fully appreciated previously because of the presence of dominant-acting perforin and Fas ligand in acute tumor cell lysis. TNF-based cytotoxicity by PKO/gld LAK was both soluble and membrane bound, and both forms of TNF were constitutively expressed. Thus, LAK cells are armed with at least three cytotoxic molecules: perforin, Fas ligand, and TNF.
从穿孔素基因敲除小鼠产生的淋巴因子激活的杀伤（LAK）细胞对一组肿瘤靶细胞系的细胞毒性显著降低，一些肿瘤细胞仅通过穿孔素途径被裂解。LAK细胞也能够介导Fas配体依赖性细胞毒性。在短期细胞毒性试验中，从同时缺乏穿孔素和Fas配体的小鼠（PKO/gld）产生的LAK细胞没有细胞溶解活性，这表明急性靶细胞裂解需要穿孔素和Fas配体。然而，PKO/gld LAK细胞在针对TNF敏感肿瘤系的长期细胞毒性试验中具有细胞毒性，并且这种细胞毒性被中和TNF抗体完全抑制。由于在急性肿瘤细胞裂解中存在起主导作用的穿孔素和Fas配体，这种强大的TNF细胞毒性以前没有得到充分认识。PKO/gld LAK基于TNF的细胞毒性是可溶性的和膜结合的，并且两种形式的TNF都是组成性表达的。因此，LAK细胞至少配备有三种细胞毒性分子：穿孔素、Fas配体和TNF。
