An adaptive natural killer (NK) cell or memory-like NK cell is a specialized natural killer cell that has the potential to form immunological memory. They can be distinguished from cytotoxic NK (cNK) cells by their receptor expression profile and epigenome. Adaptive NK cells are so named for properties which they share with the adaptive immune system. Though adaptive NK cells do not possess antigen specificity, they exhibit dynamic expansions of defined cell subsets, increased proliferation and long-term persistence for up to 3 months in vivo, high IFN-γ production, potent cytotoxic activity upon ex vivo restimulation, and protective memory responses. Adaptive NK cells have been identified in both humans and mice. Persistent adaptive NK populations have been reported during viral infection, contact hypersensitivity reactions, and after stimulation by pro-inflammatory cytokines or activating receptor pathways. IL-12, IL-18, and IL-15 contribute to the development of adaptive NK cells by priming NK cells prior to immune stimulation. Origin Human adaptive NK cells in peripheral blood are likely derived from cNK cells expressing low levels of CD56, as CD56dim cNK cells are more likely to express killer-cell immunoglobulin-like receptors (KIRs) and/or CD94/NKG2C. These surface molecules are required for antigen sensing during infection. Some evidence exists for tissue-resident adaptive NK cells in the liver, where a small population of CD49a+NKG2C+ NK cells has been shown to emerge in response to human cytomegalovirus infection. These cells differ from the predominant population of CD49a−CD49e− NK cells in the liver by their gene expression. Signals transmitted through the IL-12 receptor combined with CD2 and MHC class I-binding receptor provide a three-prong stimulation responsible for promoting the epigenetic and phenotypic modifications that occur in association with adaptive NK cell differentiation. Epigenetic regulation NK cells essentially "remember" the previous effects of cytokines. NK cells pre-activated by IL-12/15/18 transfer their enhanced IFN-γ producing capacity to daughter cells. HCMV-associated NKG2C+ adaptive NK cells and IL-12/15/18 pre-activated NK cells have been detected to have an epigenetic imprint, for instance, the demethylated CNS1 region of the IFNG gene, which in turn can lead to a remarkable stability of the IFN-γ-producing phenotype even after adoptive transfer. Both IL-12 and IL-18 are required for the pronounced demethylation of the CNS1 region, whereas IL-15 might serve as a survival factor. In addition to the IFNG gene, NKG2C+ adaptive NK cells also showed CpG demethylation of the PRDM1/BLIMP1 and ZBTB32/TZFP genes or hypermethylation of FCER1G (Fc fragment of IgE