IL-2- and IFN gamma-enhanced natural cytotoxic activity: analysis of the role of different lymphoid subsets and implications for activation routes.

To elucidate the immunoregulatory mechanisms by which human recombinant interleukin 2 (r.IL-2) and human recombinant interferon (IFN)-gamma influence natural cytotoxic activity of human peripheral blood lymphocytes (PBL), experiments were performed in which we studied: the kinetics of augmentation of natural cytotoxic activity by IL-2 and IFN-gamma; the phenotypes of the natural cytotoxic precursor cells acted upon by IL-2 and IFN-gamma; the role of IL-2-induced IFN-gamma in the natural cytotoxic activity enhancing effects of IL-2 and (d) the surface phenotypes of the natural cytotoxic cells activated by IL-2 or IFN-gamma. Three phenotypical distinct precursor cells can be identified. The phenotypes of the precursor cells sensitive to r.IFN-gamma are T3-, Leu 7+or-, FcR-gamma+. The phenotypes of the precursor cells sensitive to r.IL-2 are T3-, Leu 7-, FcR-gamma+or-. It appears that during prolonged culture relatively more of the FcR-gamma- precursor cells acquire natural cytotoxic activity upon stimulation with r.IL-2. Antibodies to IFN-gamma, known to neutralize both recombinant and natural IFN-gamma, completely inhibited the IFN-gamma-induced augmentation of natural cytotoxic activity but only slightly affected the IL-2-mediated augmentation. This indicates that only part of the augmenting effect of r.IL-2 is mediated through IL-2-induced IFN-gamma. This implies that r.IL-2 augments natural cytotoxic activity predominantly through an IFN-gamma-independent pathway. The phenotype of the effector cells expressing natural cytotoxic activity after a 4-day culture period with IL-2 or IFN-gamma was analyzed by depletion experiments. Virtually all the cells that exerted the IFN-gamma-enhanced natural cytotoxic activity are FcR-gamma+, whereas a portion of the cells that exerted the IFN-gamma-enhanced natural cytotoxic activity are FCR-gamma-. Both natural killer cells and lymphokine-activated killer cells contribute to natural cytotoxic activity. The relative contributions of both activities to the natural cytotoxic activity augmented by IL-2, respectively, IFN-gamma, is discussed.