INTERFERON-ALPHA ACTIVATES CYTOTOXIC FUNCTION BUT INHIBITS INTERLEUKIN-2 MEDIATED PROLIFERATION AND TUMOR-NECROSIS-FACTOR-ALPHA SECRETION BY IMMATURE HUMAN NATURAL-KILLER-CELLS

Natural killer (NK) cells play an important role in host defense mecha nisms against infection and neoplasia. Interferon-Lu (IFN-alpha) has b een shown to activate NK cells and to augment their cytotoxic activity , albeit its role in the maturation pathway of NK cells has not been e lucidated. The present study examined whether IFN-alpha activates the immature NK subset (Free cells) to become cytotoxic and also ascertain ed whether IFN-alpha uses the same pathway of activation as that media ted by interleukin-2 (IL-2). Incubation of sorted Free cells overnight with IFN-alpha resulted in augmentation of their cytotoxic function a gainst NK sensitive target cells. The enhanced cytotoxic activity was not accompanied by a new recruitment of NK-target binder cells but by an increase in the frequency of killer cells in the conjugate fraction . Activation of the Free subset by IFN-alpha resulted in upregulation of CD69, CD11b, and CD2 surface expression and stimulated secretion of IFN-gamma. Unlike IL-2, IFN-alpha did not stimulate the Free cells to proliferate or secrete TNF-alpha and activation of cytotoxicity and m odulation of surface antigens by IFN-alpha were independent of TNF-alp ha The failure of IFN-alpha to stimulate secretion and proliferation b y Free cells appeared to be mediated by negative signals. This was cor roborated in experiments demonstrating that when Free cells were cultu red with both IFN-alpha and IL-2, a significant inhibition was observe d for both the IL-2 dependent secretion of TNF-cu and proliferation. T hese results demonstrate that IFN-alpha serves as both an activator an d a regulator of NK function. Further, activation of the immature Free NK cells by IL-2 and IFN-alpha proceeds by TNF-alpha dependent and in dependent pathways, respectively. The findings also support our conten tion that the mechanism of activation of the cytotoxic machinery of NK cells is not linked to the mechanism of activation of cytokine secret ion and/or proliferation.