Signal transduction mechanisms in human natural killer cells mediating antitumor immunity.

The spontaneous cytotoxicity of normal human peripheral blood mononuclear cells (PBMCs) is mediated by a subset of lymphocytes called natural killer (NK) cells. Unlike other cytotoxic lymphocytes, which require prior sensitization by the specific antigen to which they are programmed to respond, single NK cells are ?irectly cytotoxic to a wide variety of mahgnant cells without prior exposure. Neither the NK cell receptor responsible for activation during this interaction nor its target cell cognate have been identified biochemically. NK cells can also be activated for lysis by the Fc region ofIgG antibodies which have coated a malignant target cell (antibody-dependent cellular cytotoxicity, ADCC). In contrast to the situation in direct cytotoxicity, the NK cell surface Fc receptor (CD16) has been well characterized and can be identified by monoclonal antibodies (mAbs) such as 3G8 and Leu-11. In this study, we used cloned, human NK cell1ines to characterize the intracellular signal transduction pathways that are used during NK cell activation. NK cells activated by direct binding of sensitive tumor cells or by Fc receptor ligation by anti-CD16 antibody demonstrated a rapid .increase in phosphoinositide hydrolysIs. Moreover, this response was modulated in a heterologous manner by the cAMP second messenger pathway, a system known to exert a significant regu~atory action on NK cell cytolytic activIty.