Interferon-mediated protection of normal and tumor target cells against lysis by mouse natural killer cells.

Abstract

Normal and tumor mouse cells treated with fibroblast type I interferon became resistant to lysis mediated by endogenous or virus- (interferon) activated mouse natural killer (NK) cells. 'Normal' cells included thymocytes, peritoneal macrophages, and fetal fibroblasts. Tumor cells and continuous cell lines protected by interferon were of various morphologies and histocompatibility types. The only cells not protected by interferon receptors, such as F-9 teratoma cells, xenogeneic Vero cells, and the interferon-selected L1210R cell variant. YAC-1 and P52 ascites cells freshly isolated from mice also were protected by interferon. Interferon protection of cells was dose dependent and was prevented by inhibitors of RNA (actinomycin D) and protein (cycloheximide) synthesis. Significant protection of L-929 cells occurred within 4 hr of treatment and lasted for over a week after removal of interferon from the culture fluid. Cold-target competition experiments suggested that NK cells did not efficiently bind to interferon-treated target cells. However, no differences were microscopially observed in the number of effector cell-target cell doublets, and monolayers of interferon-treated L929 cells clearly could deplete absorbed leukocytes of NK activity, although at a level less than untreated monolayers. In time kinetic studies, targets became resistant to lysis before their loss of cold-target competition capability, suggesting that factors other than simple binding may also play a role in resistance. Correspondingly, interferon-treated targets had somewhat reduced sensitivity to antibody-dependent cell cytotoxicity (ADCC) mechanisms, but considerable ADCC could still be achieved under conditions of near total protection of targets against NK cell-mediated lysis. In contrast, cytotoxic T cell killing was actually enhanced against interferon-treated targets, perhaps reflecting the reported increase in H-2 expression. Interferon could protect tumor cells in vivo as well as in vitro. P52 ascites cells in NK cell-deficient bg/bg mice (as well as in bg/+ littermates) became resistant to NK cell-mediated lysis if mice were injected with interferon or with an interferon-inducing virus before harvest of the ascites. Further, 125IUDR-labeled interferon-treated P52 cells were cleared from C57BL/6 mouse lung, spleen, and liver significantly less efficiently than untreated P52 tumor cells, suggesting that interferon-treated tumor cells were more resistant to host surveillance mechanisms. These data collectively suggest that an interferon-dependent mechanism potentially could inhibit tumor rejection, and this possibility should be considered when planning interferon therapy for human malignancies.