Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 1 — J Immunol 10 — J Exp Med 4 — Natural killer cell cytotoxicity: how do they pull the trigger?
Immunology 1 :7— CDa as a functional marker for the identification of natural killer cell activity. J Immunol Methods 1—2 — Granzymes are essential for natural killer cell-mediated and perf-facilitated tumor control. Eur J Immunol 32 10 —7. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.
Blood 97 1 —7. Perforin dependence of natural killer cell-mediated tumor control in vivo. Eur J Immunol 25 12 —6. Sonar S, Lal G. Thorburn A. Death receptor-induced cell killing. Cell Signal 16 2 — A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2 —9. Differential antitumor effects of administration of recombinant IL or recombinant IL are mediated primarily by Fas-Fas ligand- and perforin-induced tumor apoptosis, respectively.
NK cell-derived exosomes from NK cells previously exposed to neuroblastoma cells augment the antitumor activity of cytokine-activated NK cells. J Immunother 40 7 — Immune surveillance properties of human NK cell-derived exosomes. J Immunol 6 — Human natural killer cells produce abundant macrophage inflammatory protein-1 alpha in response to monocyte-derived cytokines. J Clin Invest 97 12 —7.
Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Cancer Res 66 1 — Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood 11 — Demonstration of an interferon gamma-dependent tumor surveillance system in immunocompetent mice. Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells. Oncoimmunology 5 12 :e Cutting edge: priming of NK cells by IL Eur J Immunol 29 9 — Interleukin and the costimulatory molecule B have a synergistic anti-tumor effect on murine melanoma; implication of combined immunotherapy for poorly immunogenic malignancy.
J Invest Dermatol 5 — Cancer Immunol Immunother 57 10 — Tolerance and alloreactivity of the Ly49D subset of murine NK cells. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat Immunol 6 9 — Champsaur M, Lanier LL. Effect of NKG2D ligand expression on host immune responses. Immunol Rev 1 — Science — A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules.
Gasser S, Raulet DH. Activation and self-tolerance of natural killer cells. Natural killer cell tolerance in mice with mosaic expression of major histocompatibility complex class I transgene. Licensing of natural killer cells by host major histocompatibility complex class I molecules. NK cell education: not an on-off switch but a tunable rheostat. Trends Immunol 30 4 —9. Identification of human memory-like NK cells. Curr Protoc Cytom Nat Immunol 11 12 — Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-alpha, interferon-gamma and interleukin Immunology 1 — Specific and nonspecific NK cell activation during virus infection.
Nat Immunol 2 10 —6. Murine NK cell intrinsic cytokine-induced memory-like responses are maintained following homeostatic proliferation. J Immunol 9 — Cytokine activation induces human memory-like NK cells. Blood 24 — Leukemia 30 2 — J Exp Med 13 — Oncoimmunology 5 9 :e Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.
Sci Transl Med 8 ra NK cells and T cells cooperate during the clinical course of colorectal cancer. Oncoimmunology 3 8 :e NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Cancer immunoediting by the innate immune system in the absence of adaptive immunity. NKG2D function protects the host from tumor initiation.
Perforin-mediated cytotoxicity is critical for surveillance of spontaneous lymphoma. J Exp Med 5 — The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res 72 6 — Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity.
Clin Immunol 3 — Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 1 —9. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment.
Cancer Res 74 24 —9. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.
N Engl J Med 23 — Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res 17 19 — Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer.
J Transl Med Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 8 —7. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients.
Blood 12 —9. Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS One 8 10 :e High-efficiency lysis of cervical cancer by allogeneic NK cells derived from umbilical cord progenitors is independent of HLA status.
Cancer Immunol Immunother 66 1 — A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 13 1 — IL enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clin Cancer Res 23 2 — Oncol Rep 37 3 — Nat Immunol 15 8 — Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin in patients with cancer.
J Clin Oncol 33 1 — Although these cytokines display some functional redundancy, their cell-specific functions during an immune response are determined by the expression of distinct receptor complexes Figure 6. Figure 6. Role of common gamma-containing receptors in natural killer NK cell development. In human, apart from its role in the early development, IL-7 also regulates the survival and expansion of mature CD56 bright NK cells.
Distinct sets of Janus kinases JAK and signal transducers and activators of transcription STAT associate and transmit the signaling from the common gamma chain-associated cytokine receptors. However, cellular affinity for either IL-2 or IL is altered by the expression of high-affinity heterotrimeric complexes containing IL-2 or ILspecific alpha subunits Given that NK cells are found near T cell areas in SLTs 10 , T cell-derived IL-2 may facilitate a vital functional crosstalk between innate and adaptive lymphocytes during an infection IL can be trans-presented by dendritic cells DCs and macrophages as well as non-hematopoietic cells including stromal cells and epithelial cells For example, T helper cells that produce IL can regulate the expression levels of activation receptors or cytolytic contents in NK cells.
Similarly, DCs that produce IL plays an essential role in the proliferation and priming of NK cells discussed in detail elsewhere in this review. Initial observations concerning hybrid resistance to NK cell-mediated transplant rejection demonstrated that F 1 hybrid mice reject transplanted BM from either parent while they do not reject transplants from other F 1 mice 85 , However, there exists a relatively small population of NK cells that do not express self-reactive inhibitory receptors under normal conditions, and these cells are hypofunctional upon stimulation The use of transgenic mouse models has led to the prevailing theories that attempt to explain the NK cell education process.
Thus, licensed NK cells are deemed functionally competent and are self-tolerant due to the interaction between inhibitory receptors and MHC-I while unlicensed NK cells, represented by those that do not express self-MHC-I-specific inhibitory receptors, are tolerant because they are functionally incompetent This may seem counterintuitive given that these receptors are known to be exclusively inhibitory; however, their designation as such was described with respect to NK cell effector functions Thus, inhibitory receptors may possess alternative functions in terms of NK cell education, and it has been demonstrated that signaling through these receptors is likely more complicated than previously appreciated While these processes are thought to control NK cell responsiveness primarily during development, new interpretations of these models suggest that they may be altered under disease conditions and function as a rheostat to set the threshold of NK cell activation in the periphery 93 , Overall, the molecular mechanisms that regulate NK cell education have yet to be described though it is clear that the NK cell education process dictates their functional capabilities.
Natural killer cells do not express clonotypic receptors. However, they mediate strong anti-tumor cytotoxicity and generate significant quantities of pro-inflammatory cytokines Expression of more than one NKR that recognize self or pathogen-derived ligands endows NK cells with inherent, innate abilities to mediate effector functions.
The varied nature of NKRs and the absence of signaling domains in their cytoplasmic tails necessitates the association and recruitment of receptor-associated adaptor molecules for signal transduction NK cell activation through these receptors occurs by interacting with distinct cellular and foreign ligands present on diseased cells and form the basis for the NK cell-mediated immune response in multiple contexts.
NKG2D is a homodimer forming C-type lectin-like type II transmembrane glycoprotein that is highly conserved from mice to humans Pharmacological or genetic inhibition of these pathways causes deficiencies in NK cell-mediated cytotoxicity and pro-inflammatory cytokine production , This finding substantiates the notion that the signaling molecules required for NK cell effector functions are not mutually exclusive and further investigation is required to fully elucidate the molecular mechanisms that regulate NK cell effector functions in response to NKG2D-mediated stimulation.
Natural killer cells mediate their immunomodulatory effects through two critical effector functions. First, NK cells are cytotoxic lymphocytes that can directly lyse cells that have undergone a malignant transformation or have become infected with a virus or other intracellular pathogen The cytolytic function of NK cells can initiate through a variety of processes, including degranulation and death receptor ligation, and is critical for the clearance of diseased and dysfunctional cells , Second, NK cells can produce a variety of inflammatory cytokines in response to activation receptor stimulation as well as inflammatory cytokine-induced activation signaling , These NK cell effector functions are essential components of the immune response and are the primary mechanisms through which NK cells mediate protective immunity.
The molecular mechanisms that regulate NK cell cytotoxicity have been well described and can be divided into three main processes: 1 target cell recognition, 2 target cell contact and immunological synapse IS formation, and 3 NK cell-induced target cell death. Distinct mechanisms have been described for how target cells are recognized by NK cells and how they deem diseased cells appropriate for destruction Figure 7. Once recognized, NK cells directly interact with the target cell of interest through the formation of a lytic IS which facilitates NK cell-induced target cell death through two essential mechanisms Figure 7.
A A brief description of the significant interactions between NK and myeloid cells. NK cells possess inherent abilities to mediate cytotoxicity and produce inflammatory cytokines and chemokines. Myeloid cell-derived cytokines play a central role in regulating the effector functions of NK cells. Interactions between the innate NK cells and the primary arms of the adaptive immunity T and B cells are less explored. Stimulation through activation receptors i. B A summary of major soluble factors produced by NK cells and their intended functions.
The first mechanism involves the activation of death receptors present on the surface of the target cell which initiates the extrinsic apoptotic pathway The death receptor superfamily is characterized by the utilization of a cytoplasmic death domain which enables these receptors to activate the apoptotic machinery including initiator caspases-8 and 10 , The apoptosome amplifies initiator caspase-mediated substrate cleavage and, along with caspaseinduced DNA fragmentation via caspase-activated DNase activation , results in cell death via apoptosis The primary mechanism of NK cell-mediated cytotoxicity involves the directed release of lytic molecules to the target cell NK cells store these molecules in cytolytic granules that are delivered to the target cell through membrane fusion at the IS This process requires cytoskeletal reorganization events including actin polymerization at the IS , as well as polarization of the microtubule organizing center toward the target cell Polarized lytic granules travel along microtubules and, once at the IS, fuse with the target cell membrane and release enzymes that facilitate that activation of the intrinsic apoptosis program within the target cell , Granzyme B and perforin are a critical component of NK cell lytic granules and is classified as an apase that cleaves peptides after aspartic acid residues Once inside the target cell, Granzyme B can trigger apoptosis through caspase-dependent and independent mechanisms.
Granzyme B activates caspase-dependent apoptosis at multiple points in the apoptotic pathway by directly cleaving the apoptotic initiator caspase-8 as well as caspase-3 , Granzyme B can also induce apoptosis in a caspase-independent manner and induce cytochrome C release from the mitochondria through the proteolytic cleavage of the pro-apoptotic protein, Bid Natural killer cells are potent producers of pro-inflammatory and immunosuppressive cytokines.
However, the release of inflammatory cytokines is distinct from cytotoxic granule secretion and NK cells utilize activation-induced signaling components to differentially regulate these two functions Although NK cells can produce a wide-range of cytokines depending on the inflammatory environment , , NK cells primarily produce Th1-type cytokines when responding to tumor ligands and intracellular pathogens , Transcriptional activation of cytolytic molecules and inflammatory cytokines is a highly regulated process mediated by a variety of transcriptional regulators in NK cells.
Many of these transcription factors, such as T-bet, are lineage defining and become activated early in NK cell development NKRs also initiate inflammatory transcriptional programs upon activation. A variety of cells generate a number of inflammatory mediators to sensitize and prime NK cells. Among these DCs play a central role A complex interplay between DCs and NK cells is defined as one of the critical steps for the sensitization of NK cells IL has both activating and inhibitory functions , and IL is an immunosuppressive cytokine produced exclusively by regulatory T cells IL is a member of the IL-1 cytokine family and signals via the IL receptor ILR through the signaling adaptors, myeloid differentiation primary response 88, and IL-1R-associated kinase , To date, the diverse functions of NK cells in mammalian immunity is not fully understood.
However, accumulating data collected from patients with rare disorders characterized by NK cell deficiency have shed light on their relevance to human health and studies using genetically modified mouse models have generated intriguing ideas with regards to their pro-inflammatory and immunosuppressive functions NK cells produce and respond to inflammatory stimuli and are most well known for their roles in anti-viral immunity and tumor immunosurveillance; however, NK cells are also involved in a variety of autoimmune disorders as drivers of pathologic inflammation Emerging evidence also demonstrates that NK cells can regulate anti-inflammatory programs, such as tissue repair , Whether NK cells act as primary innate effectors or accessory cells as part of the adaptive immune response appears to be context-dependent, but their contribution as first-line responders and essential inflammatory mediators is well established.
Natural killer cells are critical for defense against a wide variety of pathogens. Pattern recognition receptors PRRs recognize pathogen-associated molecular patterns and are essential components of the NK cell-mediated innate immune response NK cells also contribute to antifungal immunity by direct and indirect mechanisms First, NK cells can directly damage fungal membranes through the targeted release of cytotoxic granules containing the membrane disrupting protein, perforin They can also facilitate the antifungal host response through direct phagocytosis as well as the production of inflammatory mediators However, the direct contribution of NK cells to microbial immunity has best been described with regards to their discrete actions against intracellular pathogens.
Intracellular pathogens have evolved a variety of mechanisms to evade the host immune response including subversion of the MHC immunosurveillance system MHC molecules are highly polymorphic within a population and are encoded by human leukocyte antigen HLA genes in humans and, H-2 in mice Nearly all somatic cells express endogenous peptides on their surface in the context of MHC-I, and this allows the immune system to sample the intracellular environment Figure 8.
Mechanisms of target cell recognition by natural killer NK cells. NK cells lack clonotypic receptors and rely on germline-encoded activation and inhibitory receptors to recognize other cells around them. The following are some of the primary mechanisms by which NK cells perceive target cells. Natural killer cells possess unique mechanisms to contain intracellular pathogens including viruses and some species of bacteria by lysing infected cells, releasing them and exposing them to adaptive cell-mediated immunity , For example, hemagglutinin, a sialic acid receptor expressed by the influenza virus, serves as an activating ligand for NCR1 , NKG2D has also involved in NK cell-mediated anti-viral immunity as evidenced by multiple observations in which human and mouse CMV proteins downregulate cellular stress ligands that activate NK cells through this receptor — Natural killer cells have the unique ability to identify infected cells without direct engagement of the MHC-I complex 12 , However, the separation of these cells with regards to their contributions to adaptive immunity has recently been reconsidered due to the discovery of NK cells that exhibit immunological memory , Although they do not utilize clonotypic receptors, such as the TCR, a relatively small population of memory NK cells has been described as long-lived effectors capable of rapid recall responses The formation of memory NK cells has been extensively investigated in mice infected with MCMV and studies using this system have been critical in defining the molecules that mediate this phenomenon — A vaccination study using antigens from viruses including, influenza, vesicular stomatitis virus, and human immunodeficiency virus type 1 also showed memory-like NK cell responses in mice and NK cells exhibited enhanced protection against secondary infections with vaccinia virus and herpes simplex virus type 2 , Collectively, these studies provide compelling evidence demonstrating the functional relevance of NK cell memory as a universal anti-viral immune mechanism.
Observations in humans have also suggested the ability of human NK cells to form memory , ; however, the full contribution of memory NK cells to anti-viral immunity and potential implications this may have on vaccine development has yet to be determined. Natural killer cells also recognize bacteria and bacterial products either directly or from infected cells and professional APCs Figure 9 Recent work has shown that NK cells can directly release granzymes proteases to initiate disruption of electron transport, generate superoxide anion, and inactivate bacterial oxidative defenses causing the death of Listeria monocytogenes, Escherichia coli , and Mycobacteria tuberculosis — In addition, NK cells using Granzyme B mediated the killing of facultative anaerobic bacteria such as L.
Indirect killing and containment of L. Mechanisms by which NK cells mediate indirect clearance of bacteria are complex. Substantial evidence suggests that interleukins including IL and IL from monocytes and DCs play a central role — Role of other inflammatory cytokines such as IL and its cooperation with IL, IL-6, and IL during the clearance of bacterial infections have been identified; however, the precise mechanisms by which NK cells evoke the anti-microbial responses are yet to be elucidated , Figure 9.
Natural killer NK cells in health and disease. As the largest lymphocyte population representing innate immunity, NK cells perform diverse functions.
Through their ability to mediate killing and to produce soluble factors, NK cells perform multitudes of immunological functions. In addition, production of IL by NK subsets may help the regeneration of epithelial cells in the mucosal tissues.
Genetic manipulation of NK cells has helped to improve the effector functionality and the longevity of human NK cells in vivo.
Stable integration of gene encoding IL into the genome of NK cells promotes sustained proliferation via an artificial autocrine loop. Other studies have shown the expression of single chain variable fragment that forms the core ectodomain of chimeric antigen receptor CAR to augments the tumor-targeted killing of NK cells.
These genetically modified NK cells provide exciting newer opportunities for cell-based therapies. The bidirectional interaction between NK and T cells results in the regulation of adaptive immunity.
Although in vitro experiments consistently have provided support toward this notion, the in vivo evidence is far from convincing. This, in turn, plays an important role in containing the effector functions of T cells via direct binding to the NKG2D receptor expressed on T cells. NK cells recognize bacteria-infected cells such as epithelial cells either using toll-like receptors TLR or by activated through soluble factors including aryl hydrocarbon receptor Ahr.
NK cells can also directly mediate the lysis of bacteria using granzymes and perforin. The vital role of NK cells in tumor immunosurveillance was recognized soon after their initial characterization , NK cells can detect changes in surface expression of self-MHC-I molecules on autologous cells which distinctively qualifies them to detect cells that have undergone malignant transformation Figure 8 , Transformed cells also express increased numbers of stress-induced molecules on their surface which can be recognized by specific NK cell receptors, such as NKG2D , Decades of research in rodents have demonstrated the importance of NK cells in tumor clearance 14 , , , In humans, an year follow-up study showed that low NK cell cytotoxic activity was correlated to an increased risk of cancer and the presence of tumor-infiltrating NK cells is a positive prognostic marker for multiple malignancies including colorectal carcinoma , gastric carcinoma , and squamous cell lung cancer Results from multiple studies demonstrate that NK cells have promise as a cancer immunotherapeutic for the treatment of hematological malignancies including acute myeloid leukemia and acute lymphoblastic leukemia — Allogenic NK cell therapy has proven effective in the clinic and, unlike T cell-based interventions, NK cell transfusion carries a relatively low risk of adverse off-tumor effects such as graft-versus-host disease GvHD Therefore, allogeneic NK cells along with hematopoietic stem cell transplant has been explored as a potential treatment for patients with high-risk solid tumors , , Using non-myeloablative conditioning regimens to provide potent immune suppression without toxicity, the burden of cure then relies on the ability of transplanted donor cells to provide a GvT effect.
Precedence in using low-intensity conditioning before transplanting allogeneic stem cells has been reported in Ewing sarcoma — , osteosarcoma , , germ cell tumors , rhabdomyosarcoma — , neuroblastoma — , Wilms tumor , and CNS tumors , suggesting that alloreactive donor NK cells infiltrate heterogeneous solid tumors and cross the blood—brain barrier.
A sizeable reduction in tumor burden has been observed Using HLA-haploidentical family donors parents and siblings , matched by only one HLA haplotype to the patient, have not only shown favorable outcomes in patients with solid tumors , , but are also readily available and highly motivated donor sources. Thus, using HLA-haploidentical donors to augment GvT may be an effective strategy in patients undergoing allogeneic hematopoietic stem cell transplantation HCT for treatment of solid tumors , However, in addition to these, recent reports suggest NK cells also play regulatory functions , NK cells mediate regulatory functions of other cell types including myeloid [DC , — , monocytes — , and macrophages , — ] or lymphoid [T , and B — cells] via cytokines production or through direct cell—cell contact in a receptor—ligand interaction-dependent manner.
As part of the innate immune responses, effector functions of NK cells during the early phase is expected to dictate the threshold, direction, and the outcome of an immune response. These NK cell-mediated regulatory functions are predicted to occur during viral, bacterial, or protozoan infections, anti-tumor immune responses, unexpected immuno-pathological outcomes such as GvHD, and autoimmune diseases Few of the examples are described below.
Studies in both mouse and human lead to either suppressing or promoting rejection of HCT by NK cells.
Mechanistically, NK cells can help to contain GvHD through distinct mechanisms including the killing of professional APCs and thereby controlling the proliferation and expansion of graft-specific T cell , In addition, NK cells were able to directly lyse graft-specific T cells following the expression of activating ligands of NKG2D on these T cell , Also, shedding of these murine and human activating ligands has been demonstrated to employ a critical negative regulatory function on both T — and NK , cells.
These findings provide an exciting new avenue in understanding an inherent regulatory interaction between NK cell and APCs or T cells and thereby potential clinical utilization. Irrespective of the recent advances, the precise functions and associated mechanisms by which NK cells contribute to an immune-suppressive or immune-sufficient tumor microenvironment is far from fully defined.
Similarly, the complex interplay of cytokines and ILs that are derived from and regulating the functions of NK and professional APCs during viral or bacterial infections is yet to be fully appreciated. Recent efforts to improve the clinical efficacy of NK cell immunotherapy has led to the development of genetically engineered NK cells that express a chimeric antigen receptor CAR.
Through the manipulation of signaling motifs critical for lymphocyte activation, CARs are also designed to utilize specific intracellular signaling molecules which can further refine NK cell function and optimize their therapeutic potential , Interestingly, the use of a clonal cell line derived from a human NK cell leukemia, known as NK, has been genetically modified to express fully functional CARs and these cells have shown great promise with regards to their safety and efficacy in recent clinical trials , , Moreover, the use of irradiated cell lines may provide a fast and affordable off-the-shelf option for a personalized cellular immunotherapy treatment , and are quickly rising to the forefront of cell-based cancer immunotherapies Figure 9.
Natural killer cells possess promising potentials as a therapeutic tool to treat a number of maladies including malignancies In-depth understanding of NK cells at the single-cell transcriptomic landscape, methods to expand them in vitro without phenotypic and functional skewing, and detailed analyses of their in vivo longevity are central to facilitate the clinical utilization.
NK cells regulate their effector functions utilizing both activating and inhibitory receptors , Emerging evidence suggests that mNK cells possess the ability to produce both pro-inflammatory to anti-inflammatory cytokines However, the temporal regulation of these discrete functions is not yet fully understood.
NK cells can be primed in response to a wide panel of ILs and other immunomodulatory factors , , Our knowledge related to transcriptomic definitions of priming for an individual or combination of these priming factors is limited. NK cell subsets are comprised of a highly heterogeneous population A pioneering study utilizing a novel technique known as mass-cytometry CyTOF determined that there are between 6, and 30, distinct NK cell phenotypes within a given individual based on unique combinations of 35 cell surface antigens However, the functional plasticity of subsets of NK cells yet to be fully appreciated.
Collectively, the future holds promising challenges to decipher new knowledge which will facilitate the utilization of NK cells for better therapeutic outcomes. AA conceived and wrote the manuscript. CY contributed to the writing.
MT edited the text. SM conceived, wrote, and edited the text and generated all the figures for the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Oldham RK. Natural killer cells: artifact to reality: an odyssey in biology.
Cancer Metastasis Rev — Rosenau W, Moon HD. Lysis of homologous cells by sensitized lymphocytes in tissue culture. J Natl Cancer Inst — Google Scholar. Smith HJ. Antigenicity of carcinogen-induced and spontaneous tumours in inbred mice.
Together, these findings suggest that NK cells may contribute to the initiation of the autoimmune process but may be less important in established disease; however, further study is needed to confirm this conclusion.
Chronic NK cell lymphocytosis, a disorder characterized by a persistent elevation of NK cells in the peripheral blood, provides some novel insights into the potential contributions of NK cells to autoimmune disorders. Studies in both humans and mice suggest that chronic NK cell lymphocytosis results from an aberrant expansion of an immature NK cell population with functional deficits [ 79 — 81 ]. In addition to cytopenia, chronic NK cell lymphocytosis is associated with autoimmune syndromes, including vasculitis, arthritis, and peripheral neuropathy [ 82 — 84 ].
This disorder provides evidence that the dysregulation of NK cell homeostasis in the context of decreased NK cell cytotoxicity may contribute to the onset of autoimmunity. Genetic association studies in a variety of autoimmune disorders provide strong evidence that NK cells contribute to the pathogenesis of human autoimmune disorders reviewed in [ 85 , 86 ]. The KIR locus is complex with more than 20 different haplotypes encoding various numbers of inhibitory and activating KIRs, which in the context of the individual's HLA genotype influence NK cell licensing and activation [ 25 , 30 ].
MS is an inflammatory disorder that affects the central nervous system CNS. Autoreactive CD4 T cells targeting myelin components are critical mediators of the inflammatory process, particularly in the early stages of relapsing-remitting MS. However, studies in both humans and mice have implicated NK cells in the pathogenesis of MS [ 98 , 99 ]. Human NK cells are postulated to play an immunoregulatory role in MS by killing activated T cells [ ]; however, they can also directly lyse oligodendrocytes, astrocytes, and microglia through recognition of NKG2D ligands [ , ], raising the possibility that NK cells may exert either a beneficial or deleterious influence on the development of MS.
Indeed, studies in experimental autoimmune encephalomyelitis, a rodent model of MS, underscore the potential of NK cells to either suppress or augment CD4 T-cell-mediated CNS inflammation. The majority of experimental autoimmune encephalomyelitis studies have demonstrated that depletion of NK cells [ — ] or blockade of NK cell homing to the CNS via deletion of the chemokine receptor CX3CR1 [ ] resulted in severe, relapsing experimental autoimmune encephalomyelitis and increased mortality.
However, other investigators have reported that NK cell depletion resulted in less severe disease [ ] and that IL and ILmediated exacerbations of experimental autoimmune encephalomyelitis were NK cell dependent [ , ]. These results suggest that the influence of NK cells on the pathogenesis of MS is probably modulated by the inflammatory milieu, the phase of the disease, and other factors. A temporal correlation between NK cell numbers or cytotoxicity and periods of disease progression or remission in MS supports the hypothesis that NK cells may play an immunoregulatory role in disease pathology [ 77 , ].
For example, a study of relapsing-remitting MS patients demonstrated that depressed NK cell cytotoxicity preceded the appearance of contrast-enhancing CNS lesions on magnetic resonance imaging and the onset of clinical symptoms [ 77 ]. In addition, NK cells from MS patients in remission express high levels of CD95 Fas, a TNF receptor superfamily member involved in inducing apoptosis and appear to suppress auto-immune T cells [ ].
Interestingly, NK cells in the blood of MS patients lose the CD95 high phenotype during disease relapse and regain it after recovery [ ]. Paired blood and cerebrospinal fluid samples from MS patients demonstrated a substantial enrichment of CD56 bright NK cells in the cerebrospinal fluid [ ].
The daclizumab-induced increase in CD56 bright NK cells correlated with decreased magnetic resonance imaging contrast-enhancing CNS lesions in MS patients [ , ]. Taken together, the deficits in peripheral NK cell numbers in MS patients [ ], the temporal correlation between NK cell cytotoxicity and disease flares, the accumulation of CD56 bright NK cells in the cerebrospinal fluid, and the correlation of the expansion of CD56 bright NK cells with decreased flares during effective immunotherapy support the hypothesis that NK cells play an immunoregulatory role in MS.
However, definitive evidence of NK cell participation in the pathogenesis of MS will require further study. RA is a chronic autoimmune disease characterized by inflammation of joints and surrounding tissues that leads to cartilage destruction and bone erosions.
Recent studies have implicated human NK cells in the pathogenesis of RA reviewed in [ , ]. The NK cells within the synovium also showed upregulated expression of several chemokine receptors and adhesion molecules that may participate in preferential recruitment into the synovium [ 69 ]. Synovial NK cells could induce monocytes to differentiate into DCs [ ] and have also been shown to produce IL, a cytokine that induces proliferation of synovial fibroblasts [ ].
Aberrant expression of MHC class I polypeptide-related sequence A in the inflamed synovium [ ] may augment CD56 bright NK cell activation, resulting in dysregulated production of proinflammatory cytokines rather than in immunoregulation. In contrast to the accumulation of activated CD56 bright NK cells in the synovium, patients with RA have decreased circulating NK cells in their peripheral blood [ 55 ].
In addition to the numeric deficit, peripheral blood NK cells in RA patients have decreased cytotoxicity on a per-cell basis [ ]. Low numbers of peripheral blood NK cells and decreased cytotoxicity have also been identified in patients with JIA, with the most prominent deficits occurring in systemic JIA patients [ 60 , — ]. Furthermore, a significant subset of systemic JIA patients had almost a complete absence of circulating CD56 bright NK cells [ , ].
The depressed NK cell cytotoxicity in systemic JIA patients was not solely accounted for by the reduced numeric frequency of NK cells [ , ] and was associated with low levels of perforin [ , ]. Interestingly, reduced peripheral NK cell numbers and decreased cytotoxicity were also observed in the collagen-induced arthritis model [ ]. However, conclusions about the role of NK cells in regulating autoimmune arthritis in murine models must be tempered by a conflicting report that depletion of NK cells reduced the severity of arthritis and prevented bone erosions in the collagen-induced arthritis model [ ].
SLE is an immune complex-mediated disorder resulting in widespread organ dysfunction primarily in reproductive-age females. SLE is characterized by polyclonal B-cell activation and the production of a wide array of autoantibodies against nuclear proteins and DNA. Insights from murine models have implicated NK cells in the development of autoantibodies and other features of SLE [ ].
Furthermore, NK cell depletion in these mice enhanced development of autoantibody-secreting B cells while the adoptive transfer of NK cells delayed the onset of autoantibody production [ ]. Numeric deficits in peripheral NK cells have been reported in multiple cohorts of SLE patients [ 55 , 71 , — ] and correlate with clinical manifestations of SLE, including lupus nephritis and thrombocytopenia [ 55 ], and overall disease activity [ , ].
Interestingly, an increased proportion of CD56 bright NK cells has been observed in SLE patients regardless of disease activity [ ]. In addition to numeric deficits in peripheral NK cells, depressed cytotoxicity responses on a per-cell basis have been consistently documented in SLE patients [ 55 , 71 , , ] as well as in a subset of first-degree relatives [ ].
An early study in pediatric SLE patients was particularly informative since it demonstrated low numbers of peripheral NK cells and defective cytolysis on a single cell level at diagnosis or even prior to overt progression to SLE in a subset of patients [ 71 ].
By virtue of their ability to rapidly kill abnormal cells and produce cytokines and chemokines, NK cells influence and shape adaptive immune responses and are positioned to play a role in regulating autoimmune responses. Genetic association studies implicate NK cells in the pathogenesis of human autoimmune disorders.
Studies in MS, RA, and SLE, which are summarized in this review, provide tantalizing but incomplete evidence for contributions of specific subsets of NK cells in both the periphery and affected tissues to the onset or progression of autoimmunity.
The associations found in humans and the empirical evidence from murine models demonstrate that further research into the immunomodulatory role of NK cells in autoimmunity is warranted and is likely to provide novel insights into the pathogenesis of autoimmune disorders. Cell Biol. Smith, H. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. USA 99 , — Arase, H. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors.
Desrosiers, M. Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell—mediated innate resistance to cytomegalovirus infection.
Dalod, M. Biron, C. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Vidal, S. NK cell recognition of mouse cytomegalovirus-infected cells. Voigt, S. Fischer, A. Human primary immunodeficiency diseases. Immunity 27 , — Interplay of natural killer cells and their receptors with the adaptive immune response. Paya, C.
Role of natural killer cells as immune effectors in encephalitis and demyelination induced by Theiler's virus. Fairweather, D. From infection to autoimmunity. Robbins, S. Natural killer cells promote early CD8 T cell responses against cytomegalovirus. PLoS Pathog. Perforin and granzymes have distinct roles in defensive immunity and immunopathology. Janka, G. Hemophagocytic syndromes. Blood Rev. Jordan, M. Crozat, K. Jinx , an MCMV susceptibility phenotype caused by disruption of Unc13d : a mouse model of type 3 familial hemophagocytic lymphohistiocytosis.
Nedvetzki, S. Reciprocal regulation of natural killer cells and macrophages associated with distinct immune synapses. Moretta, L. Effector and regulatory events during natural killer-dendritic cell interactions. Degli-Esposti, M. Close encounters of different kinds: dendritic cells and NK cells take centre stage.
Piccioli, D. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. Yu, G. NK cells promote transplant tolerance by killing donor antigen-presenting cells. Wu, H. Martin-Fontecha, A. Morandi, B. Lu, L. Takeda, K. Johansson, S. NK cells: elusive players in autoimmunity. Yoneda, O. Fractalkine-mediated endothelial cell injury by NK cells. Bolovan-Fritts, C. Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction.
Rieben, R. Xenograft rejection: IgG1, complement and NK cells team up to activate and destroy the endothelium. Anne Croy, B. Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones. Hanna, J. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface.
Moffett, A. How does the maternal immune system contribute to the development of pre-eclampsia? Placenta 28 suppl. A , S51—S56 Dunn, C. Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage.
Chen, Y. Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology 46 , — Kerr, A. Identification of a detrimental role for NK cells in pneumococcal pneumonia and sepsis in immunocompromised hosts.
Microbes Infect. Badgwell, B. Natural killer cells contribute to the lethality of a murine model of Escherichia coli infection. Surgery , — Flodstrom, M. Target cell defense prevents the development of diabetes after viral infection. Poirot, L. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Katchar, K.
O'Leary, J. T cell— and B cell—independent adaptive immunity mediated by natural killer cells. Lambiase, A. Natural killer cells in vernal keratoconjunctivitis. Buentke, E. Natural killer and dendritic cell contact in lesional atopic dermatitis skin — Malassezia -influenced cell interaction. Ottaviani, C. Tagliabue, A. Characteristics of natural killer cells in the murine intestinal epithelium and lamina propria.
Korbel, D. Natural killer cells and innate immunity to protozoan pathogens. Roetynck, S. Natural killer cells and malaria. Mavilio, D. Alter, G. Carr, W. Vieillard, V. In vivo natural killer cell activities revealed by natural killer cell- deficient mice. USA 97 , —
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