Mechanisms of natural killer cell activation

Abstract

Cytotoxic lymphocytes are a critical effector arm of cell mediated immune responses to intracellular infections and tumors. There are two primary populations of cytotoxic lymphocytes in humans and experimental animals: cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. Both of these effector cell types are capable of recognizing and lysing aberrant or pathogenic target cells while, under most conditions, they spare normal autologous cells. This ability to discriminate between cells that will give rise to pathology in the host and normal cells is dependent on the expression of target structures for effector cell recognition and activation. For MHC-restricted, antigen-specific, CTL these target structures are primarily MHC class I molecules presenting antigenic peptides. Activation of the lytic mechanism of CTL is initiated by specific recognition of class I peptide complexes on target cells by clonally distributed T cell receptors on the CTL. In contrast, the recognition receptors of NK cells and their ligands on target cells have not been identified. Because the early activation of NK cells in an immune response has been shown to have important in vivo consequences for the host, we have investigated various mechanisms of NK cell activation to further characterize this poorly defined phenomenon. Specifically, our efforts have resulted in the identification of a novel signal transduction surface molecule expressed by human NK cells and other cytotoxic lymphocytes that is capable of inducing NK cell cytotoxicity and lymphokine production. In addition, we have investigated the specificity of human alloreactive NK clones and have established an in vitro model of murine, NK cell-mediated hybrid resistance. Finally, we have examined the ability of a newly identified cytokine, IL-12, to activate NK cells