Natural Killer (NK) cells are white blood cells initially recognized for their intrinsic ability to mediate antitumor cytotoxicity. Like CD8+ cytotoxic T cells, NK cells represent professional killer cells, but they can execute rapid killing without the need for specific immunization. NK cells are regarded as lymphocytes based on their morphology, origin, and ex
Since their initial discovery, NK cells have been found to mediate host responses to numerous pathogens, including viruses, bacteria, and parasites. NK cells can be activated by contact-dependent signals from stressed somatic cells or by pro-inflammatory cytokines, such as IL-12 and type I interferons, that are secreted by other immune cells. NK cell activation triggers release of cytotoxic granules containing perforin and granzyme B, which allow entry of apoptosis-inducing effector proteins into target cells. NK cells also express death receptor ligands, such as TNF-related apoptosis-inducing ligand (TRAIL) and Fas-L, which allow them to initiate cytolysis upon engaging death receptors on target cells. Activated NK cells are major producers of IFN-γ, in addition to other cytokines (TNF- α and IL-10), growth factors (GM-CSF and G-CSF), and chemokines that facilitate recruitment of other immune cells to sites of inflammation.
The role of NK cells in the immune response extends beyond their ability to kill harmful cells transformed by pathogens and tumors. NK cells selectively “edit” dendritic cell and macrophage populations to ensure that fully activated antigen-presenting cells display antigens to T cells and, subsequently, to attenuate the inflammatory response in a controlled fashion. NK cell-mediated cytotoxicity can also induce or modulate T cell and humoral responses. Although NK cells were originally identified for their “natural” killing abilities, optimal NK cell effector function appears to require priming by cytokines IL-12, IL-15, and IL-18, as well as other contact-dependent signals from dendritic cells, macrophages, neutrophils, and T cells. NK cell proliferation and activation is also dependent on IL-2, whose availability is promoted by CD4+ T cells and restricted by regulatory T cells. Therefore, the immune response necessitates bidirectional crosstalk between NK cells and other hematopoietic cells.
The notion that NK cells mediate rapid and short-lived responses independently of antigen specificity has grown obsolete in recent years. Immunological memory of prior pathogen encounters, which results in enhanced responses upon pathogen rechallenge, has been regarded as a unique feature of the adaptive immune response mediated by B cells and T cells. There is now evidence to suggest that long-lived NK memory populations can mediate antigen-specific recall responses. NK cells can mimic the CD8+ T cell response to murine cytomegalovirus (MCMV). Subsequent to the activation, expansion, and contraction phases of the immune response, long-lived MCMV-specific memory cells are generated that can undergo secondary expansion, rapid degranulation, and IFN-γ production upon reactivation. Memory NK cells also appear to arise in response to cytokine stimulation with IL-12, IL- 15, and IL-18. Restimulation of cytokine-induced NK memory cells results in robust IFN-γ secretion. A subset of CXCR6+ hepatic NK cells, furthermore, mediates memory in models of hapten-induced contact hypersensitivity and viral infection with antigens from HIV, influenza, and vesicular stomatitis virus (VSV). NK cells, thus, appear to straddle the border between innate and adaptive immunity.
NK cells express key receptors that regulate their activity by integrating inhibitory and activating signals transduced during interactions with target cells. When NK cells encounter cells that express major histocompatibility class I (MHC-I) molecules, their effector function is inhibited. Healthy cells with abundant MHC-I ex
There are two families of murine NK cell receptors that bind to MHC-I antigens, which include Ly49 receptors and heterodimeric CD94-NKG2 receptors. NKG2 receptors are orthologous receptors in mice and primates, while primate killer immunoglobulin-like receptors (KIRs) are the functional homologs of murine Ly49 receptors. Ly49C, Ly49I, Ly49G2, Ly49A, and CD94-NKG2A receptors signal through a common immunoreceptor tyrosine-based inhibitory motif (ITIM) in their cytoplasmic domains. Ly49 receptors exhibit distinct specificities for polymorphic MHC-I molecules, while CD94-NKG2A receptors recognize the non-classical MHC-I molecule Qa1. Because NK cells express few Ly49 receptors during early life, inhibitory interactions between CD94-NKG2A and Qa1 might contribute to the selftolerance of fetal and neonatal NK cells.
In contrast to inhibitory receptors, many activating receptors lack intracellular signaling motifs and associate with immunoreceptor tyrosine-based activating motif (ITAM)-containing adaptor proteins to propagate signals. Activating Ly49 receptors, such as Ly49D and Ly49H, are homologous to their inhibitory counterparts because they originated by gene duplication and conversion from inhibitory receptors. Therefore, activating Ly49 receptors have the ability to bind to MHC-I or MHC-I decoy molecules. Ly49H recognizes the MCMV-encoded m157 protein, an MHC-I decoy molecule, on the surface of cells infected with the virus. Mice that lack Ly49H+ NK cells to recognize MCMV-infected cells exhibited defective MCMV clearance.