NK cell phenotypic and functional heterogeneities and molecular mechanisms of cytotoxicity

Natural killer (NK) cells were discovered four decades ago, independently, by the Kiessling and Herberman groups. Since then, significant advances have accrued regarding the functional and molecular properties of NK cells as well as their clinical relevance. The important feature of NK cells is their inability to kill normal cells, while they are highly cytotoxic for infected or transformed cells. This discrimination has been largely resolved by the discovery of both activating and inhibitory receptors on NK cells and corresponding ligands on target cells. This review focuses briefly on several issues related to NK cells: (1) the phenotypic properties of NK cells, (2) the heterogeneity of NK cell activities, (3) the determination of three major NK subsets (Free, Binder, and Killer), (4) the maturation and activation of NK subsets, (5) the response of NK cells to various cytokines, (6) the target-induced inactivation and cell death of NK cells, (7) the multiple mechanisms of cell-mediated cytotoxicity, (8) the characterization of NK cytotoxic factors (NKCF), and (9) the role of membrane fluidity in cytotoxicity. These subjects are described chronologically beginning shortly after the discovery of NK cells as a result of Ron Herberman's leadership, and I am gratefully indebted to him.