IL-2- and IFNγ-enhanced natural cytotoxic activity: Analysis of the role of different lymphoid subsets and implications for activation routes

Abstract To elucidate the immunoregulatory mechanisms by which human recombinant interleukin 2 (r.IL-2) and human recombinant interferon (IFN)-γ influence natural cytotoxic activity of human peripheral blood lymphocytes (PBL), experiments were performed in which we studied: (a) the kinetics of augmentation of natural cytotoxic activity by IL-2 and IFN-γ; (b) the phenotypes of the natural cytotoxic precursor cells acted upon by IL-2 and IFN-γ; (c) the role of IL-2-induced IFN-γ 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-γ. Three phenotypical distinct precursor cells can be identified. The phenotypes of the precursor cells sensitive to r.IFN-γ are T3 − , Leu 7 +or− , FcR-γ + . The phenotypes of the precursor cells sensitive to r.IL-2 are T3 − , Leu 7 − , FcR-γ +or− . It appears that during prolonged culture relatively more of the FcR-γ − precursor cells acquire natural cytotoxic activity upon stimulation with r.IL-2. Antibodies to IFN-γ, known to neutralize both recombinant and natural IFN-γ, completely inhibited the IFN-γ-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-γ. This implies that r.IL-2 augments natural cytotoxic activity predominantly through an IFN-γ-independent pathway. The phenotype of the effector cells expressing natural cytotoxic activity after a 4-day culture period with IL-2 or IFN-γ was analyzed by depletion experiments. Virtually all the cells that exerted the IFN-γ-enchanced natural cytotoxic activity are FcR-γ + , whereas a portion of the cells exerting Il-2-enhanced natural cytotoxic activity is FcR-γ − . 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-γ, is discussed.