What is the difference between nk cells and cytotoxic t cells

Figure 5. A common schema of human natural killer NK cell development in the bone marrow and lymph nodes. A total of six distinct developmental stages have been described with Stages 2 and 4 having additional bifurcations. Stages 4a and 4b defines an entry of iNKs into mature nks, and are differentiated by the expression of NKp80 at the Stage 4b. Most important of all, CD56 expression peaks CD56 bright.

Most human NK cells in the peripheral blood are CD56 dim The downregulation of CD56 during human NK cell maturation is strongly associated with the acquisition of anti-tumor cytotoxicity as CD56 bright NK cells are potent producers of inflammatory cytokines, while the cytolytic function of human NK cells resides primarily in the CD56 dim population 58 , Cytokines are essential inflammatory mediators that control multiple aspects of NK cell biology.

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. Inhibitory receptors act as a check on NK cell killing. Once the decision is made to kill, the NK cell releases cytotoxic granules containing perforin and granzymes, which leads to lysis of the target cell. The versions or alleles of these genes a person carries have been linked to their ability to fight HIV infection and their risk of some autoimmune diseases. NK cell varieties also change with age and are affected by chronic viral infections such as cytomegalovirus CMV.

Because of their ability to kill tumour cells, NK cells are an attractive target for cancer immunotherapies. Some therapeutic monoclonal antibodies rely on NK cell killing.

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