ENHANCING EFFECT OF NATURAL-KILLER-CELL STIMULATORY FACTOR (NKSF INTERLEUKIN-12) ON CELL-MEDIATED CYTOTOXICITY AGAINST TUMOR-DERIVED AND VIRUS-INFECTED CELLS/

Natural killer cell stimulatory factor (NKSF) or interleukin-12 (IL-12 ) is a heterodimeric cytokine with pleiomorphic effects on T and NK ce lls, including induction of lymphokine production, mitogenesis, and en hancement of spontaneous cytotoxic activity. Similarly to IL-2, NKSF/I L-12 enhances NK cell-mediated cytotoxicity within a few hours and ind ependently from induced proliferation. This effect is independent from other induced cytokines, because it is not prevented by antibodies ne utralizing interferon (IFN)-alpha, IFN-beta, IFN-gamma, IL-2 or tumor necrosis factor (TNF)-alpha and, unlike the induction of IFN-gamma pro duction by peripheral blood lymphocytes, it does not require HLA class II-positive accessory cells. Enhanced cytotoxicity is accompanied by morphologic changes in NK cells, including a significant increase in t he number of cytoplasmic granules. In addition to the previously descr ibed ability to enhance the cytotoxic activity of NK cells against tum or-derived target cells, NKSF/IL-12 is also a potent stimulator of cyt otoxicity against virus-infected cells, either fibroblasts acutely inf ected with herpes viruses or T cell lines chronically infected with hu man immunodeficiency virus-1. NK cell-mediated antibody-dependent cyto toxicity or anti-CD16 antibody-redirected lysis is not significantly e nhanced by NKSF/IL-12. However, the ability of resting peripheral bloo d T cells to mediate anti-CD3 antibody-redirected lysis is enhanced by 18-h incubation with NKSF/IL-12, indicating that this lymphokine can modulate the cytotoxic capability of both NK and T cells.