Modulation of Human Natural Killer Cell Function by Cytokines and Rheumatic Disease

The activity of natural killer (NK) cells can be modified by a number of factors that either increase or suppress cytotoxicity. We have investigated in detail the cytokine induced killing of a NK resistant renal carcinoma cell line Cur by human NK cells. Preincubation of peripheral blood mononuclear cells with interferon alpha (IFNα), interleukin 2 (II-2), interleukin 1 (II-1) and tumor necrosis factor α greatly increased the rate and magnitude of Cur killing. Positively selected CD16 (+) cells were found to respond to cytokine stimulation and to mediate Cur killing. The effects of II-2 and IFNa could be upregulated by costimulation of effector cells with II-1 or TNFα. It was shown that TNFα induced II-2 receptor expression on CD16 (+) cells alone and even more in combination with II-2.Studies of NK cell function in various rheumatic diseases revealed reduced NK cytotoxicity in peripheral blood and synovial fluid (SF), both in rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). By contrast, normal NK function was found in patients with ankylosing spondylitis (AS) and psoriatic arthritis. A discordance with regard to the percentage of Leu 7 positive mononuclear cells and NK function in peripheral blood and SF was demonstrated. Minimal expression of Leu 7 positive cells and cytotoxicity was present in synovial membranes. NK function in rheumatic disease was largely independent of drug therapy.Natural killer (NK) cells are a subset of lymphocytes that mediate spontaneous cytotoxicity against certain tumor and virus infected cells without any known prior sensitation. NK lytic activity is unrestricted by the major histocompatibility complex and can be observed in short term cytotoxic assays (1). Various target cells vary in their susceptibility to NK mediated lysis suggesting that some specific recognition mechanisms are involved.NK cells are distinct from monocytes, T and B cells and appear morphologically like large granular lymphocytes (LGL). Spontaneous cytotoxicity against K562 is almost exclusively mediated by a CD3 (-), CD16 (+) LGL (1,2).Apart from playing a role in the unspecific defense mechanisms against microbial infections and cancer, NK cells also function as suppressors of a variety of immune responses, including B cell differentiation and antibody synthesis (3,4).