What does it take to make a natural killer?

Natural killer (NK) cells respond to cytokines, stress signals, microbial products and molecules that are expressed on infected or transformed cells. They are therefore important in the defence against infection and cancer. Although it is generally accepted that NK-cell generation takes place in the bone marrow of adults, the features that make the bone marrow well suited for NK-cell development remain ill-defined. Haematopoietic stem cells (HSCs) successively restrict their potential to generate different blood cell lineages. Recently, commited NK-cell progenitors (NKPs) have been identified. A two-step stromal cell-free culture system has defined the minimal cytokine requirements for NK-cell generation in vitro. In a first phase, HSCs become committed to the NK-cell lineage; and in the second phase, they become killer cells under the influence of interleukin-15. The final maturation of NK cells, including acquisition of expression of MHC-specific inhibitory and activating receptors, depends on contact with stromal cells. A better understanding of NK-cell development could improve the use of these effector cells in diverse pathological states.