Natural killer cell subsets: maturation, differentiation and regulation.

Studies of the maturation and differentiation of human peripheral blood-derived natural killer (NK) cells were examined on isolated three subsets of NK cells. These subsets were separated based on their ability to bind and/or kill the target cells. Flow cytometry and cell-sorting analyses enabled the separation of free, binder and killer cells. These three subsets were subjected to various phenotypic and functional analyses. The findings suggest that the three subsets belong to the same lineage of maturation and differentiation, e.g. free and binders can mature into killer cells. The killer cells are not terminally differentiated as they respond to IL-2 and targets and proliferate. The response of free cells to IL-2 and IFN-alpha proceeds by distinct pathways, namely IL-2-mediated activation and proliferation is under the control of endogenous TNF-alpha production but not IFN-alpha-mediated activation. Regulation of several surface markers' expression is associated with functional maturation. In addition to activation, the cells can also undergo inactivation or anergy following interaction with targets. The binder and killer cells are the predominant subsets that become inactivated for cytotoxicity and their response to IL-2 is inhibited. The studies also show that various events associated with activation of cytotoxicity are under different regulatory controls than those for proliferation and secretion. These studies suggest that biochemical and molecular events associated with signalling and differentiation are now possible to unravel using the NK subsets.