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

Journal article
Authors Markus Hansson
Ana Romero
Fredrik Bergh Thorén
Svante Hermodsson
Kristoffer Hellstrand
Published in J Leukoc Biol
Volume 76
Issue 6
Pages 1207-13
ISSN 0741-5400 (Print)
Publication year 2004
Published at Institute of Laboratory Medicine, Dept of Clinical Virology
Pages 1207-13
Language en
Keywords Antigens, CD/immunology, Antigens, CD3/immunology, Antigens, Differentiation, T-Lymphocyte/immunology, Apoptosis/drug effects/immunology, Cell Communication/physiology, Cells, Cultured, Cytotoxicity, Immunologic/drug effects/immunology, Enzyme Inhibitors/pharmacology/therapeutic use, Free Radical Scavengers/pharmacology/therapeutic use, Humans, Immune Tolerance/drug effects/ immunology, Interferon-alpha/ pharmacology, Killer Cells, Natural/drug effects/immunology, Leukocytes, Mononuclear/immunology/metabolism/secretion, Lymphocyte Activation/drug effects/ immunology, Lymphocytes/drug effects/ immunology, NADPH Oxidase/antagonists & inhibitors/metabolism, Oxidative Stress/drug effects/immunology, Phagocytes/ immunology/metabolism/secretion, Reactive Oxygen Species/ immunology/metabolism, T-Lymphocytes, Cytotoxic/drug effects/immunology
Subject categories Medical and Health Sciences


A significant part of the therapeutic benefit of interferon-alpha (IFN-alpha) therapy in malignant diseases and in chronic viral infections is assumed 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 frequently impaired. Mononuclear phagocyte (MP)-derived reactive oxygen species (ROS) have been proposed to contribute to the lymphocyte suppression in these tissues. Here, we report that three types of human cytotoxic lymphocytes of relevance to immunoactivation by IFN-alpha, CD3epsilon+/8+/56- T cells, CD3epsilon-/56+ NK cells, and CD3epsilon+/56+ NK/T cells became anergic to IFN-alpha induction of the cell-surface activation marker CD69 after exposure to autologous MPs in vitro. In addition to their incapacity to express CD69, cytotoxic lymphocytes acquired features characteristic of apoptosis after incubation with MPs. The lymphocyte apoptosis and nonresponsiveness to IFN-alpha were prevented by two inhibitors of reduced nicotinamide adenine dinucleotide phosphate oxidase-dependent formation of ROS in MPs, histamine dihydrochloride and diphenylene ionodonium, as well as by catalase, a scavenger of ROS. We conclude that MP-derived ROS may negatively affect IFN-alpha-induced immunostimulation and propose that ROS inhibitors or scavengers may be useful to improve lymphocyte activation during treatment with IFN-alpha.

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