CHANGES OF LIVER-RESIDENT NK CELLS DURING LIVER-REGENERATION IN RATS

To determine the role of NK cells in regulation of tissue growth, the phenotype and Function of liver-resident NK cells were studied after 7 0% partial hepatectomy in rats. The process of liver regeneration was generally completed by day 14. In contrast, the number of liver-reside nt NK cells (NKR-P1(bright)) was restored as early as day 3 after part ial hepatectomy. However, spontaneous functions of liver-resident NK c ells, including killing of YAC-1 and P815 targets, Ab-dependent eel lu lar cytotoxicity, and redirected killing via NKR-P1, were continuousl y 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 s timulation showed a similar pattern of suppression. However, IL-2-indu ced augmentation of YAC-1 killing, proliferation and generation of adh erent NK cells, and LAK activity in 5- to 7-day cultures were found to he suppressed only during the first 24 h and increased between days 2 and 7 after hepatectomy. Sorted NK cells (greater than or equal to 95 % NKR-P1(bright)) from liver-resident mononuclear leukocytes 24 h afte r partial hepatectomy showed the same pattern of suppression as unsort ed mononuclear leukocytes. In contrast to liver-resident NK cells, no significant changes were detected in peripheral blood or spleen NK cel ls of rats following partial hepatectomy. Of particular interest, in n ormal liver, hepatocytes were resistant to NK lysis, while resident NK cells were cytotoxic for various NK-sensitive targets. In contrast, d uring the early period of liver regeneration, when hepatocytes were se nsitive to lysis by liver-resident NK cells of normal rats, NK cells o btained from regenerating liver tissues were unable to mediate cytotox icity. At the final phase of liver regeneration (days 7-14 after hepat ectomy), both resistance of hepatocytes to killing by NK cells and cyt otoxicity of liver-resident lymphocytes against hepatocytes from regen erating liver were simultaneously restored. In vivo depletion of NK ce lls by injection of rats with anti-NKR-P1 mAb resulted in a significan t augmentation of liver regeneration subsequent to partial hepatectomy . Our data suggest that liver-resident NK cells may be involved in reg ulation of the extent of liver regeneration.