The 'T-cell-ness' of NK cells: unexpected similarities between NK cells and T cells

NK cells are considered as prototypical innate immune cells. However, recent discoveries have tended to refine the dogmatic concepts of innate and adaptive immunity. In many ways, NK cells are highly related to T cells and represent the closest innate immune cell lineage to adaptive immune cell populations. Here, we review the relationships between NK cells and T cells and discuss the recently described cell-intrinsic-adaptive features of NK cells.     

Innate lymphocyte and dendritic cell cross-talk: a key factor in the regulation of the immune response

Dendritic cells (DC) are specialized in the presentation of antigens and the initiation of specific immune responses. They have been involved recently in supporting innate immunity by interacting with various innate lymphocytes, such as natural killer (NK), NK T or T cell receptor (TCR)-gammadelta cells. The functional links between innate lymphocytes and DC have been investigated widely and different studies demonstrated that reciprocal activations follow on from NK/DC interactions. The cross-talk between innate cells and DC which leads to innate lymphocyte activation and DC maturation was found to be multi-directional, involving not only cell-cell contacts but also soluble factors. The final outcome of these cellular interactions may have a dramatic impact on the quality and strength of the down-stream immune responses, mainly in the context of early responses to tumour cells and infectious agents. Interestingly, DC, NK and TCR-gammadelta cells also share similar functions, such as antigen uptake and presentation, as well as cytotoxic and tumoricidal activity. In addition, NK and NK T cells have the ability to kill DC. This review will focus upon the different aspects of the cross-talk between DC and innate lymphocytes and its key role in all the steps of the immune response. These cellular interactions may be particularly critical in situations where immune surveillance requires efficient early innate responses.     

Cytokine-activated natural killer cells exert direct killing of hepatoma cells harboring hepatitis C virus replicons.

Hepatitis C virus (HCV)-specific impairments in host immunity have been described at multiple levels of the innate and adaptive response, which may lead to viral persistence in the majority of infections. Understanding of HCV-associated immune defects could lead to novel therapeutic advances. Natural killer (NK) cells, the major effector cells of the innate immune system, are functionally impaired in chronic HCV infection. It has been suggested that this phenotype is a result of virus-specific defects in antigen-presenting cells (APCs) that regulate NK cell activity, as normal NK function is restored when they are stimulated ex vivo. In this study, we used human NK cell cytotoxicity assays to evaluate the activation-induced effects of NK cells on the HCV replicon-containing hepatic cells. We found that cytokine-activated NK cells were capable of inducing an HCV-associated, perforin/granzyme-dependent lysis of human hepatoma cells and that this required direct cellular contact and was independent of MHC class I expression levels. In contrast, on removal of cytokine stimulation, NK cells failed to exert any direct cytolytic effect on replicon targets. These findings suggest an important underlying mechanism by which NK cells control HCV infection and, with appropriate understanding of HCV-associated immune defects, could lead to novel therapeutic advances.     

Human NK cell response to pathogens

NK cells represent important effectors of the innate immunity in the protection of an individual from microbes. During an NK-mediated anti-microbial response, the final fate (survival or death) of a potential infected target cell depends primarily on the type and the number of receptor/ligand interactions occurring at the effector/target immune synapse. The identification of an array of receptors involved in NK cell triggering has been crucial for a better understanding of the NK cell biology. In this context, NCR play a predominant role in NK cell activation during the process of natural cytotoxicity. Regarding the NK-mediated pathogen recognition and NK cell activation, an emerging concept is represented by the involvement of TLRs and activating KIRs.NK cells express certain TLRs in common with other innate cell types. This would mean that specific TLR ligands are able to promote the simultaneous and synergistic stimulation of these innate cells, providing a coordinated mechanism for regulating the initiation and amplification of immune responses.Evidences have been accumulated indicating that viral infections may have a significant impact on NK cell maturation, promoting the expansion of phenotypically and functionally aberrant NK cell subpopulations. For example, during chronic HIV-infection, an abnormal expansion of a dysfunctional CD56neg NK cell subset has been detected that may explain, at least in part, the defective NK cell-mediated antiviral activity. An analogous imbalance of NK cell subsets has been detected in patients receiving HSCT to cure high risk leukemias and experiencing HCMV infection/reactivation. Remarkably, NK cells developing after CMV reactivation may contain “memory-like” or “long-lived” NK cells that could exert a potent anti-leukemia effect.     

Regulation of adaptive immunity by natural killer cells

Natural killer (NK) cells are well recognized as cytolytic effector cells of the innate immune system. In the past several years, the structure and function of NK cell receptors for the major histocompatibility complex (MHC) class I molecules and other ligands have been the subject of extensive studies. These studies have focused largely on the mechanisms of target cell recognition for lysis. Another aspect of NK cell function that seems to be underappreciated is their role in immune regulation. Since NK cells produce a number of immunologically relevant cytokines, it has been suggested that these cells may modulate the development of the adaptive immune response. But, is it the only mechanism by which NK cells interact with cells involved in the induction of antigen-specific responses? This article reviews some older and more recent studies and attempts to place NK cells in the context of potent immune regulators of T cell responses.     

Natural killer cell receptors and their ligands in liver diseases

The liver is a distinctive immune organ with predominant innate immunity, being rich in innate immune cells such as natural killer (NK) cells. In humans, NK cells comprise about 30%–50% of intrahepatic lymphocytes, whereas peripheral blood lymphocytes contain about 5%–20% NK cells. Accumulating evidence suggests that NK cells play an important role not only in host defense against invading microorganisms and tumor transformation in the liver but also in liver injury and repair. In recent years, significant progress has been made in terms of understanding how NK cells recognize their target cells and carry out their effector functions. It is now clear that NK cells are strictly regulated by numerous activating and inhibitory NK cell receptors that recognize various classes of cell surface ligands, some of which are expressed by normal healthy cells. Therefore, to further elucidate the involvement of NK cells in the pathogenesis of liver diseases, an understanding of recent advances in NK cell biology is crucial. This review provides an overview of recent advances in our knowledge of human NK cell receptors and their ligands in the context of liver diseases.     

Memory-like responses of natural killer cells

Summary: Natural killer (NK) cells are lymphocytes with the capacity to produce cytokines and kill target cells upon activation. NK cells have long been categorized as members of the innate immune system and as such have been thought to follow the ‘rules’ of innate immunity, including the principle that they have no immunologic memory, a property thought to be strictly limited to adaptive immunity. However, recent studies have suggested that NK cells have the capacity to alter their behavior based on prior activation. This property is analogous to adaptive immune memory; however, some NK cell memory-like functions are not strictly antigen dependent and can be demonstrated following cytokine stimulation. Here, we discuss the recent evidence that NK cells can exhibit properties of immunologic memory, focusing on the ability of cytokines to non-specifically induce memory-like NK cells with enhanced responses to restimulation.     

Activation of natural killer cells: underlying molecular mechanisms revealed

Natural killer (NK) cells, the third major lymphocyte population, are important effector cells against certain infections and tumours. They have also been implicated as a link between innate and adaptive immune responses. In recent years, much attention has been paid to the NK cell inhibitory receptors and their interaction with major histocompatibility complex class I molecules on target cells. This review summarizes recent findings on regulation of NK cell activity with an emphasis on NK cell stimulatory receptors. A particular emphasis is devoted to the receptor NKG2D that is expressed on all NK cells.     

自然杀伤细胞活化性受体的研究进展

自然杀伤细胞（NK）是机体固有免疫系统的重要效应细胞,其不仅能杀死病毒感染细胞和肿瘤细胞,还参与调节固有免疫应答和适应性免疫应答.NK细胞对靶细胞的杀伤效应取决于NK细胞抑制性受体和活化性受体与其配体相互作用的整合,而NK细胞不杀伤正常组织是因为抑制性受体对HLA-Ⅰ类分子的优势识别.NK细胞抑制性受体研究比较成熟,近几年NK细胞活化性受体研究进展很快.     

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Human NK cells are innate immune effectors that play a critical roles in the control of viral infection and malignancy. The importance of their homeostasis and function can be demonstrated by the study of patients with primary immunodeficiencies (PIDs), which are part of the family of diseases known as inborn defects of immunity. While NK cells are affected in many PIDs in ways that may contribute to a patient's clinical phenotype, a small number of PIDs have an NK cell abnormality as their major immunological defect. These PIDs can be collectively referred to as NK cell deficiency (NKD) disorders and include effects upon NK cell numbers, subsets, and/or functions. The clinical impact of NKD can be severe including fatal viral infection, with particular susceptibility to herpesviral infections, such as cytomegalovirus, varicella zoster virus, and Epstein‐Barr virus. While NKD is rare, studies of these diseases are important for defining specific requirements for human NK cell development and homeostasis. New themes in NK cell biology are emerging through the study of both known and novel NKD, particularly those affecting cell cycle and DNA damage repair, as well as broader PIDs having substantive impact upon NK cells. In addition, the discovery of NKD that affects other innate lymphoid cell (ILC) subsets opens new doors for better understanding the relationship between conventional NK cells and other ILC subsets. Here, we describe the biology underlying human NKD, particularly in the context of new insights into innate immune cell function, including a discussion of recently described NKD with accompanying effects on ILC subsets. Given the impact of these disorders upon human immunity with a common focus upon NK cells, the unifying message of a critical role for NK cells in human host defense singularly emerges.     

Natural killer cells remember: An evolutionary bridge between innate and adaptive immunity?

Since their discovery three decades ago, NK cells have been classified as cells of the innate immune system. NK cells were shown to respond rapidly and non‐specifically to infection, and were thought to act as a functional “bridge” to sustain the early innate immune response until the later adaptive immune responses could be mounted. In light of new findings showing how NK cells possess nearly all of the features of adaptive immunity including memory, we propose the placement of NK cells as an “evolutionary bridge” between innate and adaptive immunity.     

Role of natural killer cells in HIV pathogenesis

Although the majority of research on immune cell recognition of HIV-infected cells has focused on CD8⁺ T cells with an eye towards vaccine development, innate immune recognition by natural killer (NK) cells has become a focus in recent years. Genetic and mechanistic data indicate that NK cells play a role during pathogenesis, and research on NK biology in the context of the broader immune response shows that NK cells are required to mount an effective antiviral response. HIV is able to escape cytotoxic T lymphocyte recognition by downmodulation of major histocompatibility complex class I receptors, which should enhance NK cytotoxicity against infected targets. However, the virus has evolved elaborate mechanisms to evade NK cell responses. Moreover, NK cell function as a whole is compromised through poorly understood mechanisms as a result of viremia. Further work on the role of NK cells during all stages of disease will further our understanding of the immune response against HIV.     

Elevated frequency of gamma interferon-producing NK cells in healthy adults vaccinated against influenza virus

Recent studies indicate that innate immunity in influenza virus infection is an area of substantial importance for our understanding of influenza virus pathogenesis, yet our knowledge of the mechanisms controlling innate immunity remains limited. Further delineation of the roles of NK cells and innate immunity in viral infection may have important implications for the development of improved influenza virus vaccines. In this study, we evaluated the phenotype and function of NK and T lymphocytes, as well as influenza virus-specific immunoglobulin G production, prior to and following vaccination with the routinely administered trivalent influenza virus vaccine. We demonstrate influenza virus antigen-specific innate and adaptive cellular responses and evaluate changes in NK cell receptor expression over time. Our results demonstrate increased innate and adaptive cellular immune responses and show that NK cells are a significant source of gamma interferon (IFN-γ) following influenza virus vaccination. An increase in the frequency of IFN-γ-producing NK cells was observed in many subjects postvaccination. The subset distribution with respect to CD56^dim and CD56^bright NK cell subsets remained stable, as did the NK cell phenotype with respect to expression of cell surface activating and inhibitory receptors. These results may form the basis for further investigations of the role of NK cells in immunity to influenza.     

Early liaisons between cells of the innate immune system in inflamed peripheral tissues

The crosstalk between natural killer (NK) cells and myeloid dendritic cells (DCs) results in NK-cell activation and DC maturation. Activated NK cells acquire the ability to kill DCs that have failed to undergo complete maturation ('DC editing'). Recent studies have revealed that this crosstalk can be promoted by pathogen-derived products that activate different innate immune cell types directly and simultaneously through their Toll-like receptors (TLRs). These cells include NK cells and DCs, as well as plasmacytoid DCs (PDCs) and mast cells. This crosstalk can have a great impact on the quality and strength of the subsequent adaptive immune response. Thus, NK cells have an important role in the defense against pathogens, acting as regulatory cells as well as effector cells.     

The role of natural killer cells in tumor control—effectors and regulators of adaptive immunity

Natural killer (NK) cells are the primary effector cells of the innate immune system and have a well-established role in tumor rejection in a variety of spontaneous and induced cancer models. NK cell function is regulated by a complex balance of inhibitory and activating signals that allow them to selectively target and kill cells that display an abnormal pattern of cell surface molecules, while leaving normal healthy cells unharmed. In this review we discuss NK cell function, the role of NK cells in cancer therapies, the emerging concept of bi-directional cross-talk between NK cells and dendritic cells, and the implications of these interactions for tumor immunotherapy.     

The role of natural killer cells in tumor control--effectors and regulators of adaptive immunity

Natural killer (NK) cells are the primary effector cells of the innate immune system and have a well-established role in tumor rejection in a variety of spontaneous and induced cancer models. NK cell function is regulated by a complex balance of inhibitory and activating signals that allow them to selectively target and kill cells that display an abnormal pattern of cell surface molecules, while leaving normal healthy cells unharmed. In this review we discuss NK cell function, the role of NK cells in cancer therapies, the emerging concept of bi-directional cross-talk between NK cells and dendritic cells, and the implications of these interactions for tumor immunotherapy.     

Control of NK cell functions by CD4+CD25+ regulatory T cells

Regulatory T cells (Treg) are key players in the maintenance of peripheral tolerance. As a result of suppressive effects on CD4+ and CD8+ effector T cells, Treg control the adaptive immune system and prevent autoimmunity. In addition, they inhibit B lymphocytes, dendritic cells, and monocytes/macrophages. It is interesting that several recent papers show that CD4+CD25+ Treg are also able to inhibit NK cells. Thus, Treg exert their control on immune responses from the onset (triggering of innate immune cells) to the effector phase of adaptive immunity (B and T cell-mediated responses). That Treg inhibit NK cells suggests that their uncontrolled activation might break self-tolerance and induce "innate" autoimmune pathology. Conversely, Treg-mediated suppression of NK cell functions might have negative effects, as these cells are important in defense against infections and cancer. It is conceivable that Treg might dampen efficient activation of NK cells in these diseases.     

Natural killer cell memory

Natural killer (NK) cells are bone marrow–derived granular lymphocytes that have a key role in immune defense against viral and bacterial infections and malignancies. NK cells are traditionally defined as cells of the innate immune response because they lack RAG recombinase–dependent clonal antigen receptors. However, evidence suggests that specific subsets of mouse NK cells can nevertheless develop long-lived and highly specific memory to a variety of antigens. Here we review published evidence of NK cell–mediated, RAG-independent adaptive immunity. We also compare and contrast candidate mechanisms for mammalian NK cell memory and antigen recognition with other examples of RAG-independent pathways that generate antigen receptor diversity in non-mammalian species and discuss NK cell memory in the context of lymphocyte evolution.