Tumor necrosis factor-α enhances cytolytic activity of human natural killer cells

The effect of recombinant tumor necrosis factor-α (rTNFα) on human natural killer (NK) function was examined. Lysis of both the NK-sensitive K562 erythroleukemia line and the relatively insensitive renal carcinoma line Cur by nonadherent peripheral blood lymphocytes was significantly enhanced as a result of an 18-hr preincubation with either rTNFα or recombinant interleukin 2 (rIL 2). When cells were preincubated with rTNFα and low doses of rIL 2 (1 to 10 U/ml), marked additional augmentation of lysis of both targets was noted which was greater than that caused by either cytokine alone. Similar results were observed when responses of CD16⁺ large granular lymphocytes selected with the fluorescence-activated cell sorter after staining with the NK-specific monoclonal antibody Leu-11 were examined, indicating that the action of the cytokines was directly on the cytotoxic cells. Augmentation of tumor cell lysis could not be ascribed to a cytolytic activity of rTNFα on the targets, because no combination of rIL 2, rTNFα, or interferon-α caused lysis of K562 or Cur. By flow cytometric analysis, it was found that expression of IL 2 receptors was induced on purified CD16⁺ large granular lymphocytes by rTNFα alone and to an even greater degree by the combination of rTNFα and rIL 2. Additional analysis of the expression of surface antigens and blocking studies with monoclonal antibodies showed that enhanced tumor cell lysis was not caused by the augmentation of leukocyte function-associated antigen-1-mediated effector/target interactions. These data indicate that rTNFα alone, or in combination with rIL 2, directly augments NK cytotoxic activity.