Vujanovic N L, Polimeno L, Azzarone A, Francavilla A, Chambers W H, Starzl T E, Herberman R B, Whiteside T L
Department of Pathology, University of Pittsburgh School of Medicine, PA, USA.
J Immunol. 1995 Jun 15;154(12):6324-38.
To determine the role of NK cells in regulation of tissue growth, the phenotype and function of liver-resident NK cells were studied after 70% partial hepatectomy in rats. The process of liver regeneration was generally completed by day 14. In contrast, the number of liver-resident NK cells (NKR-P1bright) was restored as early as day 3 after partial hepatectomy. However, spontaneous functions of liver-resident NK cells, including killing of YAC-1 and P815 targets, Ab-dependent cellular cytotoxicity, and redirected killing via NKR-P1, were continuously suppressed throughout the entire period of liver regeneration (from 3 h to 14 days). Augmentation of NK cytotoxicity against P815 targets and induction of NK cell adherence to plastic following 24 h of IL-2 stimulation showed a similar pattern of suppression. However, IL-2-induced augmentation of YAC-1 killing, proliferation and generation of adherent NK cells, and LAK activity in 5- to 7-day cultures were found to be suppressed only during the first 24 h and increased between days 2 and 7 after hepatectomy. Sorted NK cells (> or = NKR-P1bright) from liver-resident mononuclear leukocytes 24 h after partial hepatectomy showed the same pattern of suppression as unsorted mononuclear leukocytes. In contrast to liver-resident NK cells, no significant changes were detected in peripheral blood or spleen NK cells of rats following partial hepatectomy. Of particular interest, in normal liver, hepatocytes were resistant to NK lysis, while resident NK cells were cytotoxic for various NK-sensitive targets. In contrast, during the early period of liver regeneration, when hepatocytes were sensitive to lysis by liver-resident NK cells of normal rats, NK cells obtained from regenerating liver tissues were unable to mediate cytotoxicity. At the final phase of liver regeneration (days 7-14 after hepatectomy), both resistance of hepatocytes to killing by NK cells and cytotoxicity of liver-resident lymphocytes against hepatocytes from regenerating liver were simultaneously restored. In vivo depletion of NK cells by injection of rats with anti-NKR-P1 mAb resulted in a significant augmentation of liver regeneration subsequent to partial hepatectomy. Our data suggest that liver-resident NK cells may be involved in regulation of the extent of liver regeneration.
为了确定自然杀伤（NK）细胞在组织生长调节中的作用，我们研究了大鼠70%部分肝切除术后肝内驻留NK细胞的表型和功能。肝再生过程一般在第14天完成。相比之下，肝内驻留NK细胞（NKR-P1bright）的数量早在部分肝切除术后第3天就开始恢复。然而，肝内驻留NK细胞的自发功能，包括对YAC-1和P815靶细胞的杀伤、抗体依赖性细胞毒性以及通过NKR-P1介导的重定向杀伤，在整个肝再生期间（从3小时到14天）持续受到抑制。白细胞介素-2（IL-2）刺激24小时后，NK细胞对P815靶细胞的细胞毒性增强以及NK细胞对塑料的黏附诱导呈现出类似的抑制模式。然而，发现IL-2诱导的对YAC-1的杀伤增强、黏附性NK细胞的增殖和生成以及在5至7天培养物中的淋巴因子激活的杀伤细胞（LAK）活性仅在最初24小时受到抑制，并在肝切除术后第2天至第7天之间增加。部分肝切除术后24小时从肝内驻留单核白细胞中分选的NK细胞（≥NKR-P1bright）表现出与未分选的单核白细胞相同的抑制模式。与肝内驻留NK细胞不同，部分肝切除术后大鼠外周血或脾脏NK细胞未检测到显著变化。特别有趣的是，在正常肝脏中，肝细胞对NK细胞溶解具有抗性，而驻留NK细胞对各种NK敏感靶细胞具有细胞毒性。相反，在肝再生早期，当肝细胞对正常大鼠肝内驻留NK细胞的溶解敏感时，从再生肝组织中获得的NK细胞无法介导细胞毒性。在肝再生的最后阶段（肝切除术后第7至14天），肝细胞对NK细胞杀伤的抗性以及肝内驻留淋巴细胞对再生肝肝细胞的细胞毒性同时恢复。通过给大鼠注射抗NKR-P1单克隆抗体在体内清除NK细胞，导致部分肝切除术后肝再生显著增强。我们的数据表明，肝内驻留NK细胞可能参与肝再生程度的调节。
