Effect of virus infections on target cell susceptibility to natural killer cell-mediated lysis.

By using two types of target cells (L-929, Vero) infected with several different viruses (Herpes simplex, lymphocytic choriomeningitis, Sendai, Sindbis, and vesicular stomatitis) that code for proteins expressed on the cell surface, the interactions of natural killer (NK) cells with virus-infected target cells were examined. When cells were exposed to normal endogenous spleen leukocytes from C3H/St mice, elevated (but low levels of) natural killing was usually observed against virus-infected but not uninfected targets. At least 8 hr were required for cytotoxicity to develop, and all results were consistent with the hypothesis that NK cells were activated during the incubation procedure, as shown in the human system by Santoli et al. Exposure of virus-infected cells to spleen leukocyte preparations taken from LCMV-infected mice and thus containing activated NK cells resulted in a strikingly different effect. If short-term (4 hr) assays were run to avoid additional NK cell activation by interferon, virus-infected targets were frequently less sensitive to natural killing than control cells. This apparent paradox is explained by the fact that virus infections that activate NK cells may also protect targets. HSV-infected Vero cells resisted NK cell lysis, failed to bind lymphocytes in target binding assays, and were poor competitors in cold target inhibition assays, indicating that they no longer expressed a functional NK target antigen. Sendai virus-infected L-929 cells resisted NK cell lysis but bound lymphocytes to an enhanced degree and acted as excellent cold target competitors. Thus, these cells bound activated NK cells but were not lysed by them. Nevertheless, these same cells were sensitive to antibody-mediated cell cytotoxicity. This indicates that NK cells must bind to targets by way of specialized receptors in order to kill, and that binding simply via a viral surface protein will not suffice. Interferon treatment rendered L-929 cells resistant to natural killing and unable to inhibit in competition assays. Although interferon effects may explain the resistance of virus-infected L-929 cells, they cannot explain the resistance of HSV-infected Vero cells. Such cells have probably lost their NK receptor by way of viral alterations of cellular metabolic machinery. In one system (Sendai virus in Vero cells), enhanced sensitivity to activated NK cells concomitant to enhanced target cell binding was observed. In other systems (e.g., LCMV in L-929 cells) no in vitro activation of NK cells or protection of target cells was observed. Taken together, these results indicate that the interactions between NK cells and virus-infected targets are complex and vary with the virus, target cell, and extent of infection.