Intimate cell conjugate formation and exchange of membrane lipids precede apoptosis induction in target cells during antibody-dependent, granulocyte-mediated cytotoxicity
Intimate cell conjugate formation and exchange of membrane lipids precede apoptosis induction in target cells during antibody-dependent, granulocyte-mediated cytotoxicity
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DOI：
10.4049/jimmunol.179.1.337
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发表时间：
2007-07-01
影响因子：
4.4
通讯作者：
Stockmeyer, Bernhard
中科院分区：
文献类型：
--
作者：
Horner, Heike;Frank, Carola;Stockmeyer, Bernhard
Ab依赖的多形粒细胞（PMN）介导的细胞毒作用可能在恶性疾病的控制中发挥重要作用。然而，很少有人知道哪些特定的途径用于杀伤恶性细胞的PMN。已观察到活性氧中间体（ROI）的产生在Ab依赖性细胞介导的细胞毒性（ADCC）期间发生。然而，中性粒细胞，从慢性肉芽肿病患者表现出强大的ADCC对恶性淋巴瘤细胞。此外，抑制健康供体PMN中ROI的产生对ADCC没有显著影响。因此，由PMN的NADPH氧化酶产生的ROI对于PMN介导的ADCC似乎不是强制性的。最近的数据表明穿孔素在PMN介导的细胞毒性中的作用。然而，在我们的试验中，孔卡霉素A，穿孔素介导的ADCC的单核细胞的抑制剂，对中性粒细胞介导的ADCC没有抑制作用。使用电子显微镜，我们观察到，中性粒细胞和它们的靶细胞密切相互作用，形成相互交错的膜突起。在中性粒细胞和靶细胞接触有一个相互交换的荧光膜脂质染料，强烈增加的肿瘤靶向抗体的存在下。这一观察结果可能与最近描述的淋巴细胞胞啃过程密切相关。瞬时PMN-肿瘤细胞聚集体的存在和PMN与肿瘤细胞衍生的膜脂质的积累，反之亦然与有效的ADCC相关，如通过铬释放或凋亡诱导所测量的。
Ab-dependent polymorphonuclear granulocyte (PMN)-mediated cytotoxicity may play an important role in the control of malignant diseases. However, little is known as to which particular pathways are used for the killing of malignant cells by PMN. The production of reactive oxygen intermediates (ROI) has been observed to occur during Ab-dependent, cell-mediated cytotoxicity (ADCC). However, PMN,from a patient with chronic granulomatous disease demonstrated strong ADCC against malignant lymphoma cells. Furthermore, the inhibition of ROI production in PMN from healthy donors had no significant effect on ADCC. Therefore, ROI production by the NADPH oxidase of PMN does not appear to be mandatory for PMN-mediated ADCC. Recent data suggest a role for perforins in PMN-mediated cytotoxicity. However, in our assays concanamycin A, an inhibitor of perforin-mediated ADCC by mononuclear cells, had no inhibitory effect on PMN-mediated ADCC. Using electron microscopy we observed that PMN and their target cells intimately interact with the formation of interdigitating membrane protrusions. During PMN and target cell contact there was a mutual exchange of fluorescent membrane lipid dyes that was strongly increased in the presence of tumor-targeting Abs. This observation may be closely related to the recently described process of trogocytosis by lymphocytes. The presence of transient PMN-tumor cell aggregates and the accumulation of PMN with tumor cell-derived membrane lipids and vice versa were associated with effective ADCC as measured by chromium-release or apoptosis induction.