Cytokine regulation of natural killer cell effector functions

Initially described as effectors of natural cytotoxicity and critical players for the control of viral infections and tumor growth, recent investigations unraveled more widespread functions for the natural killer (NK) cells. Through the establishment of a crosstalk with dendritic cells, NK cells promote T helper-1- and cytotoxic T lymphocyte-mediated immunity, whereas through the establishment of a crosstalk with macrophages, NK cells contribute to the activation of their microbicidal functions. Recent evidence has shown that NK cells also display memory, a characteristic thought to be privative of T and B cells, and that NK cells acquire their mature phenotype during a complex ontogeny program which tunes their activation threshold. Cytokines play critical roles in regulating all aspects of immune responses, including lymphoid development, homeostasis, differentiation, tolerance, and memory. Cytokines such as interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and type I interferons constitute pivotal factors involved in the maturation, activation, and survival of NK cells. In addition, the discovery of novel cytokines is increasing the spectrum of soluble mediators that regulate NK cell immunobiology. In this review, we summarize and integrate novel concepts about the role of different cytokines in the regulation of NK cell function. We believe that a full understanding of how NK cells become activated and develop their effector functions in response to cytokines and other stimuli may lead to the development of novel immunotherapeutic strategies for the treatment of different types of cancer, viral infections, and chronic autoimmune diseases.