In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing ‘memory’ NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.

During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94–NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56^dimCD16⁺NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94–NKG2C receptor and CD57 in CMV⁺donors. These CD57⁺NKG2C^hiNK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57⁺NKG2C^hiNK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57⁺NKG2C^hiNK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C⁺NK cells proliferated, became NKG2C^hi, and finally acquired CD57. Thus, we propose that CD57 might provide a marker of “memory” NK cells that have been expanded in response to infection.

Natural killer (NK) cells are innate immune lymphocytes that express a heterogeneous repertoire of germline-encoded receptors and undergo a distinct pattern of maturation. CD57 is a marker of terminal differentiation on human CD8+ T cells. Very few newborn or fetal NK cells express CD57; however, the frequency of CD57-bearing NK cells increases with age. We assessed the transcriptional, phenotypic, and functional differences between CD57+ and CD57− NK cells within the CD56dim mature NK subset. CD57+ NK cells express a repertoire of NK-cell receptors, suggestive of a more mature phenotype, and proliferate less when stimulated with target cells and/or cytokines. By contrast, a higher frequency of CD57+ NK cells produced interferon-γ and demonstrated more potent lytic activity when these cells were stimulated through the activating receptor CD16; however, they are less responsive to stimulation by interleukin-12 and interleukin-18. Finally, CD57 expression is induced on CD57−CD56dim NK cells after activation by interleukin-2. A combination of a mature phenotype, a higher cytotoxic capacity, a higher sensitivity to stimulation via CD16, with a decreased responsiveness to cytokines, and a decreased capacity to proliferate suggest that CD57+ NK cells are highly mature and might be terminally differentiated.

NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8⁺ T cells, and subsets of CD4⁺ T cells, invariant NKT cells (iNKT), and γδ T cells. In humans, NKG2D transmits signals by its association with the DAP10 adapter subunit, and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least eight genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and posttranslation. In general, healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyperproliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves as a mechanism for the immune system to detect and eliminate cells that have undergone “stress.” Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system, and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases. Cancer Immunol Res; 3(6); 575–82. ©2015 AACR.