INTERFERON - A MAJOR REGULATOR OF NATURAL-KILLER CELL-MEDIATED CYTOTOXICITY

Natural killer (NK) cells probably function as an early defense line a gainst viruses because of their ability to kill virus-infected cells a s well as a variety of tumor cells. In both cases, the killing is majo r histocompatibility complex (MHC)-unrestricted. NK cells exhibit spon taneous activity but they are positively regulated by interferons (IFN s) or indirectly by such IFN inducers as viruses, bacterial products, poly(rI):(rC), and mitogens. In addition to their ''positive'' regulat ion on NK activity, IFNs often act as ''negative signals'' for NK and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. If NK su sceptible target cells are exposed to IFN prior to NK cells, their sen sitivity to NK activity is often markedly diminished. The mechanism by which IFNs (IFN-alpha, -beta, and -gamma) affect the sensitivity of t arget cells to NK activity remains unknown, but it is clear that this function is not shared by other cell-mediated killing processes. The p rotective effect induced by IFN against NK activity is dependent on ne w mRNA and protein synthesis and can be abolished when target cells ar e incubated with a combination of IFN and metabolic inhibitors or by c hemotherapeutic purine or pyrimidine analogs. IFN treatment neither af fects the conjugate formation between NK cell and target cell nor the susceptibility of target cells to NK cytotoxic factor (NKCF), released by effector cells. However, IFN reduces the capacity of target cells to induce activation of conjugated NK cells. Because IFN has the abili ty to induce or increase class I MHC antigen expression (on NK target cells), it has been suggested that class I MHC antigens act as ''negat ive signals'' or NK-mediated cytotoxicity. Although many studies suppo rt this hypothesis, others present evidence for a lack of involvement of class I MHC antigens in mediating sensitivity to NK activity. This review summarizes and discusses the dual effect of IFNs in the regulat ion of NK activity, the relationship between the expression of class I MHC antigens on target cell surface and sensitivity to NK activity fo llowing treatment with IFNs, and the possible clinical relevance of th e dual effect of IFN.