Activation of cytotoxic lymphocytes by interferon-α: role of oxygen radical-producing mononuclear phagocytes

A significant part of the therapeutic benefit of interferon- (IFN-) therapy in malig- nant diseases and in chronic viral infections is as- sumed to result from activation of lymphocytes with natural killer (NK) and T cell phenotype. In tumor tissue and in chronically infected tissue, the function and viability of these lymphocytes are fre- quently impaired. Mononuclear phagocyte (MP)- derived reactive oxygen species (ROS) have been proposed to contribute to the lymphocyte suppres- sion in these tissues. Here, we report that three types of human cytotoxic lymphocytes of relevance to immunoactivation by IFN-, CD3/8/56 - T cells, CD3- /56 NK cells, and CD3/ 56 NK/T cells became anergic to IFN- induction of the cell-surface activation marker CD69after expo- sure to autologous MPs in vitro. In addition to their incapacity to express CD69, cytotoxic lympho- cytes acquired features characteristic of apoptosis after incubation with MPs. The lymphocyte apo- ptosisand nonresponsiveness to IFN- were pre- vented by two inhibitors of reduced nicotinamide adenine dinucleotide phosphateoxidase-dependent formation of ROS in MPs, histamine dihydrochlo- ride and diphenylene ionodonium, as well as by catalase, a scavenger of ROS. We conclude that MP-derived ROS may negatively affect IFN--in- duced immunostimulationand propose that ROS inhibitors or scavengers may be useful to improve lymphocyte activation during treatment with IFN-. J. Leukoc. Biol. 76: 1207-1213; 2004.