Natural killer (NK) cells are non-T, non-B cell lymphocytes that lyse a variety of tumor and virus-infected cells. In this study, we demonstrated that phytohemagglutinin (PHA) rendered resistant autologous T cells extremely sensitive to natural-killer(NK)-cell-mediated lysis. The sensitization was very rapid and concentration-dependent (0.01-1 microg/ml); 62% and 95% of autologous T cells were lysed by interleukin-2-activated NK cells 5 min and 18 h respectively after treatment with PHA (1 microg/ml). The maximal decrease in the level of MHC class I molecules observed on T cells was 22%. Induction of susceptibility to NK-mediated lysis was correlated with the expression of activation markers on T cells treated for relatively long intervals (more than 18 h) with high concentrations of PHA (more than 0.1 microg/ml). Sensitization of T cells required RNA and protein synthesis, although DNA synthesis was not essential. We propose that this unique system is suitable for studying the mechanisms involved in recognition and killing of target cells by NK cells.