Figure 1.

Mechanisms of natural killer (NK)-cell activation resulting in the induction of NK-mediated immunological memory. Upon activation by a variety of stimuli, “naïve” NK cells adopt a memory phenotype, characterized by the capacity to mount a qualitatively and/or quantitatively enhanced immune response to secondary exposure to the same (or a similar) stimulus. The type of memory NK cell elicited depends on the activating stimulus. For example, certain inflammation-induced cytokines, specifically interleukin (IL)-2, IL-15, and IL-18, acting on NK-cell-expressed cytokine receptors (middle, left) induce memory-like NK cells that are not restricted to specific antigens (Ags). Infection with certain viruses (such as mouse cytomegalovirus  [MCMV] in C57BL6 mice) induces expression of virally encoded recognition motifs (e.g., MCMV-m157) and other activating distress signals (e.g., NKG2D ligands) on the host-cell surface that are recognized by germline-encoded NK cell receptors (NKRs; e.g., Ly49H). Finally, some NK cells have the capacity to specifically recognize and remember highly diverse microbial or hapten-based immunizing Ags presented by dendritic cells and other antigen-presenting cells (APCs). The receptor(s) used by NK cells to detect such Ags (Ag-R) are as yet undefined. It should be noted that although a single naïve NK cell is shown to give rise to memory in response to all stimuli, naïve NK cells actually comprise a large variety of discrete subsets, and the ability to generate specific types of memory varies greatly between subsets.