by which cells display viral or tumor antigens to cytotoxic t cells. a common evolutionary adaptation to this is seen in both intracellular microbes and tumors: the chronic down-regulation of mhc i molecules, which makes affected cells invisible to t cells, allowing them to evade t cell-mediated immunity. nk cells apparently evolved as an evolutionary response to this adaptation (the loss of the mhc eliminates cd4/cd8 action, so another immune cell evolved to fulfill the function). tumor cell surveillance natural killer cells often lack antigen-specific cell surface receptors, so are part of innate immunity, i.e. able to react immediately with no prior exposure to the pathogen. in both mice and humans, nks can be seen to play a role in tumor immunosurveillance by directly inducing the death of tumor cells (nks act as cytolytic effector lymphocytes), even in the absence of surface adhesion molecules and antigenic peptides. this role of nk cells is critical to immune success particularly because t cells are unable to recognize pathogens in the absence of surface antigens. tumor cell detection results in activation of nk cells and consequent cytokine production and release. if tumor cells do not cause inflammation, they will also be regarded as self and will not induce a t cell response. a number of cytokines are produced by nks, including tumor necrosis factor α (tnfα), ifnγ, and interleukin (il-10). tnfα and il-10 act as proinflammatory and immunosuppressors, respectively. the activation of nk cells and subsequent production of cytolytic effector cells impacts macrophages, dendritic cells, and neutrophils, which subsequently enables antigen-specific t and b cell responses. instead of acting via antigen-specific receptors, lysis of tumor cells by nk cells is mediated by alternative receptors, including nkg2d, nkp44, nkp46, nkp30, and dnam. nkg2d is a disulfide-linked homodimer which recognizes a number of ligands, including ulbp and mica, which are typically expressed on tumor cells. the role of dendritic cell—nk cell interface in immunobiology have been studied and defined as critical for the comprehension of the complex immune system. nk cells, along with macrophages and several other cell types, express the fc receptor (fcr) molecule (fc-gamma-riii = cd16), an activating biochemical receptor that binds the fc portion of igg class antibodies. this allows nk cells to target cells against which a humoral response has been gone through and to lyse cells through antibody-dependant cytotoxicity (adcc). this response depends on the affinity of the fc receptor expressed on nk cells, which can have high, intermediate, and low affinity for the fc portion of the antibody. this affinity is determined by the amino acid in position 158 of the protein, which can be phenylalanine (f allele) or valine (v allele). individuals with high-affinity fcrgammriii (158 v/v allele) respond better to antibody therapy. this has been shown for lymphoma patients who received the antibody rituxan. patients who express the 158 v/v allele had a better antitumor response. only 15–25% of the population expresses the 158 v/v allele. to determine the adcc contribution of monoclonal antibodies, nk-92 cells (a "pure" nk cell line) has been transfected with the gene for the high-affinity fcr. clearance of senescent cells natural killer cells (nk cells) and macrophages play a major role in clearance of senescent cells. natural killer cells directly kill senescent cells, and produce cytokines which activate macrophages which remove senescent cells. natural killer cells can use nkg2d receptors to detect senescent cells, and kill those cells using perforin pore-forming cytolytic protein. cd8+ cytotoxic t-lymphocytes also use nkg2d receptors to detect senescent cells, and promote killing similar to nk cells. for example, in patients with parkinson's disease, levels of natural killer cells are elevated as they degrade alpha-synuclein aggregates, destroy senescent neurons, and attenuate the neuroinflammation by leukocytes in the central nervous system. adaptive features of nk cells—"memory-like", "adaptive" and memory nk cells the ability to generate memory cells following a primary infection and the consequent rapid immune activation and response to succeeding infections by the same antigen is fundamental to the role that t and b cells play in the adaptive immune response. for many years, nk cells have been considered to be a part of the innate immune system. however, recently increasing evidence suggests that nk cells can display several features that are usually attributed to adaptive immune cells (e.g. t cell responses) such as dynamic expansion and contraction of subsets, increased longevity and a form of immunological memory, characterized by a more potent response upon secondary challenge with the same antigen. in mice, the majority of research was carried out with murine cytomegalovirus (mcmv) and in models of hapten-hypersensitivity reactions. especially, in the mcmv model, protective memory functions of mcmv-induced nk cells were discovered and direct recognition of the mcmv-ligand m157 by the receptor ly49 was demonstrated to be crucial for the generation of adaptive nk cell responses. in humans, most studies have focused on the expansion of an nk cell subset carrying the activating receptor nkg2c (klrc2). such expansions were observed primarily in response to human cytomegalovirus (hcmv), but also in other infections including hantavirus, chikungunya virus, hiv, or viral hepatitis. however, whether these virus infections trigger the expansion of adaptive nkg2c+ nk cells or whether other infections result in re-activation of latent hcmv (as suggested for hepatitis ), remains a field of study. notably, recent research suggests that adaptive nk cells can use the activating receptor nkg2c (klrc2) to directly bind to human cytomegalovirus-derived peptide antigens and respond to peptide recognition with activation, expansion, and differentiation, a mechanism of responding to virus infections that was previously only known for t cells of the adaptive immune system. nk cell function in pregnancy as the majority of pregnancies involve two parents who are not tissue-matched, successful pregnancy requires the mother's immune system to be suppressed. nk cells are thought to be an important cell type in this process. these cells are known as "uterine nk cells" (unk cells) and they differ from peripheral nk cells. they are in the cd56bright nk cell subset, potent at cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral cd56bright nk cells, with a slightly different receptor profile. these unk cells are the most abundant leukocytes present in utero in early pregnancy, representing about 70% of leukocytes here, but from where they originate remains controversial. these nk cells have the ability to elicit cell cytotoxicity in vitro, but at a lower level than peripheral nk cells, despite containing perforin. lack of cytotoxicity in vivo may be due to the presence of ligands for their inhibitory receptors. trophoblast cells downregulate hla-a and hla-b to defend against cytotoxic t cell-mediated death. this would normally trigger nk cells by missing self recognition; however, these cells survive. the selective retention of hla-e (which is a ligand for nk cell inhibitory receptor nkg2a) and hla-g (which is a ligand for nk cell inhibitory receptor kir2dl4) by the trophoblast is thought to defend it against nk cell-mediated death. uterine nk cells have shown no significant difference in women with recurrent miscarriage compared with controls. however, higher peripheral nk cell percentages occur in women with recurrent miscarriages than in control groups. nk cells secrete a high level of cytokines which help mediate their function. nk cells interact with hla-c to produce cytokines necessary for trophoblastic proliferation. some important cytokines they secrete include tnf-α, il-10, ifn-γ, gm-csf and tgf-β, among others. for example, ifn-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. nk cell evasion by tumor cells by shedding decoy nkg2d soluble ligands, tumor cells may avoid immune responses. these soluble nkg2d ligands bind to nk cell nkg2d receptors, activating a false nk response and consequently creating competition for the receptor site. this method of evasion occurs in prostate cancer. in addition, prostate cancer tumors can evade cd8 cell recognition due to their ability to downregulate expression of mhc class 1 molecules. this example of immune evasion actually highlights nk cells' importance in tumor surveillance and response, as cd8 cells can consequently only act on tumor cells in response to nk-initiated cytokine production (adaptive immune response). excessive nk cells experimental treatments with nk cells have resulted in excessive cytokine production, and even septic shock. depletion of the inflammatory cytokine interferon gamma reversed the effect. applications anticancer therapy tumor-infiltrating nk cells have been reported to play a critical role in promoting drug-induced cell death in human triple-negative breast cancer. since nk cells recognize target cells when they express nonself hla antigens (but not self), autologous (patients' own) nk cell infusions have not shown any antitumor effects. instead, investigators are working on using allogeneic cells from peripheral blood, which requires that all t cells be removed before infusion into the patients to remove the risk of graft versus host disease, which can be fatal. this can be achieved using an immunomagnetic column (clinimacs). in addition, because of the limited number of nk cells in blood (only 10% of lymphocytes are nk cells), their number needs to be expanded in culture. this can take a few weeks and the yield is donor-dependent. nk-92 cells a more efficient way to obtain high numbers of nk cells is to expand nk-92 cells, an nk cell line with all the characteristics of highly active blood natural killer (nk) cells but with much broader and higher cytotoxicity. nk-92 cells grow continuously in culture and can be expanded to clinical-grade numbers in bags or bioreactors. clinical studies have shown nk-92 cells to be safe and to exhibit anti-tumor activity in patients with lung or pancreatic cancer, melanoma, and lymphoma. because nk-92 cells originated from a patient with lymphoma, they must be irradiated prior to infusion. although efforts are being made to engineer the cells to eliminate the need for irradiation. the irradiated cells maintain full cytotoxicity. nk-92 are allogeneic (from a donor different from the recipient), but in clinical studies have not been shown to elicit significant host reaction. unmodified nk-92 cells lack cd-16, making them unable to perform antibody-dependent cellular cytotoxicity (adcc); however, the cells have been engineered to express a high affinity fc-receptor (cd16a, 158v) genetically linked to il-2 that is bound to the endoplasmic reticulum (er). these high affinity nk-92 cells can perform adcc and have greatly expanded therapeutic utility. nk-92 cells have also been engineered to expressed chimeric antigen receptors (cars), in an approach similar to that used for t cells. an example of this is an nk-92 derived cell engineered with both a cd16 and an anti-pd-l1 car; currently in clinical development for oncology indications a clinical grade nk-92 variant that expresses a car for her2 (erbb2) has been generated and is in a clinical study in patients with her2 positive glioblastoma. several other clinical grade clones have been generated expressing the cars for pd-l1, cd19, her-2, and egfr. pd-l1 targeted high affinity nk cells have been given to a number of patients with solid tumors in a phase i/ii study, which is underway. nkg2d-fc fusion protein in a study at boston children's hospital, in coordination with dana–farber cancer institute, in which immunocompromised mice had contracted lymphomas from ebv infection, an nk-activating receptor called nkg2d was fused with a stimulatory fc portion of the ebv antibody. the nkg2d-fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients. in a transplantation model of lmp1-fueled lymphomas, the nkg2d-fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients. in hodgkin lymphoma, in which the malignant hodgkin reed-sternberg cells are typically hla class i deficient, immune evasion is in part mediated by skewing towards an exhausted pd-1hi nk cell phenotype, and re-activation of these nk cells appears to be one mechanism of action induced by checkpoint-blockade. new findings innate resistance to hiv recent research suggests specific kir-mhc class i gene interactions might control innate genetic resistance to certain viral infections, including hiv and its consequent development of aids. certain hla allotypes have been found to determine the progression of hiv to aids; an example is the hla-b57 and hla-b27 alleles, which have been found to delay progression from hiv to aids. this is evident because patients expressing these hla alleles are observed to have lower viral loads and a more gradual decline in cd4+ t cells numbers. despite considerable research and data collected measuring the