IL-18–conditioned NK cells (yellow) migrate to the T cell (blue) zones of lymph nodes.

On page 941, Mailliard et al. show that natural killer (NK) cells exposed to the cytokine interleukin (IL)-18 commit to a life of helping rather than killing. According to the study, IL-18 creates interferon (IFN)-γ–producing, T helper (Th)-1–promoting NK cells, whereas IL-2 spawns killers.

NK cells are innate immune cells known for their ability to kill transformed or infected cells and to secrete cytokines including IFN-γ. Recently, these cells have been shown to influence the adaptive immune response by interacting with dendritic cells (DCs), thereby triggering either DC maturation or death. But the signals that determine whether NK cells kill DCs or help them mature are not completely understood. Also unknown is whether functionally specialized subsets of NK cells exist or whether individual NK cells are capable of different functions depending on the circumstances.Mailliard and colleagues now show that IL-18 and IL-2 induce distinct pathways of human NK cell differentiation. IL-18 induced the expression of the chemokine receptor CCR7 on NK cells and the production of IFN-γ, without affecting the ability of the NK cells to kill target cells. IL-2, on the other hand, increased NK cell killing activity but did not induce the expression of CCR7. Interactions between IL-18–conditioned NK cells and DCs increased IFN-γ production by the NK cells and IL-12 production by the DCs, both cytokines that promote Th1 responses.

The authors propose that IL-18–conditioned NK cells would be well suited to migrate to draining lymph nodes after activation in vivo, as lymph node entry depends on CCR7 expression. Once there, these cells might help amplify Th1 responses by interacting with DCs. By contrast, IL-2–conditioned NK cells, which killed DCs in vitro, are more likely to terminate the immune response by eliminating antigen-expressing DCs once the adaptive immune response has done its job.