Characterization of natural killer cell phenotype and function during recurrent human HSV-2 infection

Human natural killer (NK) cell differentiation, characterized by a loss of NKG2A in parallel with the acquisition of NKG2C, KIRs, and CD57 is stimulated by a number of virus infections, including infection with human cytomegalovirus (CMV), hantavirus, chikungunya virus, and HIV-1. Here, we addressed if HSV-2 infection in a similar way drives NK cell differentiation towards an NKG2A(-)NKG2C(+)KIR(+)CD57(+) phenotype. In contrast to infection with CMV, hantavirus, chikungunya virus, and HIV-1, recurrent HSV-2 infection did not yield an accumulation of highly differentiated NK cells in human peripheral blood. This outcome indicates that human HSV-2 infection has no significant imprinting effect on the human NK cell repertoire.     

Interleukin-10 suppresses natural killer cell but not natural killer T cell activation during bacterial infection

Interleukin (IL)-10 is an anti-inflammatory cytokine known to modulate the outcome of sepsis by decreasing pro-inflammatory cytokine production, including IL-12, a main activator of natural killer (NK) cells. We hypothesized that neutralization of IL-10 would increase NK and natural killer T (NKT) cell activation through increased IL-12 in a mouse model of bacterial peritonitis. NK and NKT cell activations were measured by CD69 expression on NK1.1+/CD3- and NK1.1+/CD3+ cells after cecal ligation and puncture (CLP). NK cells were significantly more activated in mice treated with anti-IL-10 antibodies, whereas no such effect was observed in NKT cells. Similarly, intracellular interferon gamma (IFN-gamma) levels were increased in NK cells of anti-IL-10-treated mice, but not in NKT cells. IL-12 and IL-18 levels were increased in both CLP groups, but in anti-IL-10-treated mice, early IL-12 and late IL-18 levels were significantly higher than in controls. Survival at 18 h after CLP was lower in anti-IL-10 mice, which was associated with increased liver neutrophil accumulation. In summary, these data show an activating effect of IL-10 on NK, but not on NKT cells after CLP, which corresponded with decreased survival, higher IFN-gamma production, and increased remote organ neutrophil accumulation. These effects were not mediated by IL-12 and IL-18 alone, and reinforce a role for NK cells in remote organ dysfunction following peritonitis.     

Activating and inhibitory receptors and their role in natural killer cell function

Last decade has seen a significant advancement in our understanding of the Natural Killer (NK) cell biology and function. Several receptors present on NK cells have been identified, which are involved in either their activation or inhibition. Similarly, a large number of interacting ligands have been identified on the target cells that upon interaction transmit either activating or inhibitory signals. This review is oriented towards understanding the role of these receptors on the NK cells, which are considered as the first line of defense.     

Unravelling natural killer cell function: triggering and inhibitory human NK receptors

Natural killer (NK) cells represent a highly specialized lymphoid population characterized by a potent cytolytic activity against tumor or virally infected cells. Their function is finely regulated by a series of inhibitory or activating receptors. The inhibitory receptors, specific for major histocompatibility complex (MHC) class I molecules, allow NK cells to discriminate between normal cells and cells that have lost the expression of MHC class I (e.g., tumor cells). The major receptors responsible for NK cell triggering are NKp46, NKp30, NKp44 and NKG2D. The NK-mediated lysis of tumor cells involves several such receptors, while killing of dendritic cells involves only NKp30. The target-cell ligands recognized by some receptors have been identified, but those to which major receptors bind are not yet known. Nevertheless, functional data suggest that they are primarily expressed on cells upon activation, proliferation or tumor transformation. Thus, the ability of NK cells to lyse target cells requires both the lack of surface MHC class I molecules and the expression of appropriate ligands that trigger NK receptors.     

Virus-driven evolution of natural killer cell receptors

Natural killer (NK) cells can mount an immediate response against viral infection, secreting cytokines and killing virus-infected cells. However, viruses have devised strategies to avoid immune detection. Here, we discuss NK cell recognition of viruses and propose that viruses may provide the evolutionary pressure causing the diversification of the NK cell receptors.     

The evolution of natural killer cell receptors

Natural killer (NK) cells are immune cells that play a crucial role against viral infections and tumors. To be tolerant against healthy tissue and simultaneously attack infected cells, the activity of NK cells is tightly regulated by a sophisticated array of germline-encoded activating and inhibiting receptors. The best characterized mechanism of NK cell activation is “missing self” detection, i.e., the recognition of virally infected or transformed cells that reduce their MHC expression to evade cytotoxic T cells. To monitor the expression of MHC-I on target cells, NK cells have monomorphic inhibitory receptors which interact with conserved MHC molecules. However, there are other NK cell receptors (NKRs) encoded by gene families showing a remarkable genetic diversity. Thus, NKR haplotypes contain several genes encoding for receptors with activating and inhibiting signaling, and that vary in gene content and allelic polymorphism. But if missing-self detection can be achieved by a monomorphic NKR system why have these polygenic and polymorphic receptors evolved? Here, we review the expansion of NKR receptor families in different mammal species, and we discuss several hypotheses that possibly underlie the diversification of the NK cell receptor complex, including the evolution of viral decoys, peptide sensitivity, and selective MHC-downregulation.     

自然杀伤细胞受体的研究进展

自然杀伤细胞（ＮＫ细胞）可表达两类功能相悖的识别受体,即活化受体（ＫＡＲ）和抑制受体（ＫＩＲ）。ＫＩＲ能识别自身细胞上的ＭＨＣⅠ类分子与自身或外来肽形成２的复合物,所产生的抑制信号可阴断ＫＡＲ的活化,以此抑制ＮＫ细胞的细胞毒作用。如果靶细胞失去ＫＩＲ所识别的配体,ＮＫ细胞即可通过ＫＡＲ对靶细胞进行攻击。本文将介绍此类受体的结构及基识别与信号转导机制的研究进展。     

Alternative mechanisms of natural killer cell activation during herpes simplex virus infection

Although NK cells can kill both malignant cells and virus-infected cells without prior sensitization, it has remained unclear whether the mechanism by which an NK cell is activated in the presence of a tumor cell is similar to that induced by the presence of a virus-infected cell. In our experimental system using homogeneous populations of cloned human CD16+ NK cells, we found that HSV-infected target cells do not induce in the NK cells the same pharmacologically-active second messengers elicited by NK-sensitive tumor cells. Although phosphoinositide turnover and calcium signaling were generated in NK cells exposed to NK-sensitive tumor cells, the recognition of HSV-infected cells by NK cells did not result in similar transmembrane signaling. Furthermore, depending on the cell type infected by HSV, alternative mechanisms of cytotoxicity were employed. HSV-infected foreskin fibroblasts were rapidly and selectively killed by cloned NK cells without a requirement for IFN or accessory cells. In contrast to this direct cytotoxicity against HSV-infected foreskin fibroblasts, NK cell-mediated cytotoxicity against an HSV-infected fibrosarcoma cell line (1591) was dependent on IFN-alpha production by accessory cells. Importantly, in both systems of cytotoxicity, IFN-alpha activation of NK cells resulted in augmented killing against both infected and uninfected targets. These results suggest that NK cell activation induced during antiviral immunity is distinct from activation elicited during an antitumor response. These differences include the utilization of alternative forms of signal transduction and alternative mechanisms of cytotoxicity.     

Glucocorticoids regulate natural killer cell function epigenetically

Although glucocorticoids are well known for their capacity to suppress the immune response, glucocorticoids can also promote immune responsiveness. It was the purpose of this investigation to evaluate the molecular basis for this apparent dichotomous immunologic effect. Glucocorticoid treatment of natural killer cells (NK) was shown to reduce NK cell cytolytic activity by reduction of histone promoter acetylation for perforin and granzyme B, which corresponded with reduced mRNA and protein for each. In contrast, glucocorticoid treatment increased histone acetylation at regulatory regions for interferon gamma and IL-6, as well as chromatin accessibility for each. This increase in histone acetylation was associated with increased proinflammatory cytokine mRNA and protein production upon cellular stimulation. These immunologic effects were evident at the level of the individual cell and demonstrate glucocorticoids to epigenetically reduce NK cell cytolytic activity while at the same time to prime NK cells for proinflammatory cytokine production.     

Exercise stress and murine natural killer cell function

Male C3He mice were trained to run on a treadmill (final speed, slope, and duration of 30 m/min, 8 degrees, 30 min/day, 5 days/week, respectively) for 10 weeks or they remained sedentary. At the end of the training program, half of the mice were sacrificed and half were given a single bout of exercise to exhaustion (50% stepwise increases in final running speed for 2-min intervals). Splenic catecholamine concentrations, splenic natural killer cell cytolytic activity against YAC-1 tumor targets, and frequency of asialo GM1 (a murine natural killer cell surface glycolipid)-positive splenocytes were assessed. Exhaustive exercise in both trained and untrained mice reduced the in vitro killing of tumor targets by splenic natural killer cells relative to killing by splenocytes from mice which did not undergo the acute exercise bout (P less than 0.05). The frequency of asialo GM1-positive splenocytes was also reduced in the exhaustively exercised animals (P less than 0.05). Training alone, without the additional stress of exhaustive exercise, reduced the frequency of asialo GM1-positive splenocytes relative to a sedentary condition (P less than 0.05), but did not compromise natural killer cell cytolytic activity against the tumor targets. Splenic epinephrine concentrations in the exhaustively exercised animals were elevated 3- to 5-fold above the concentrations observed in trained and sedentary mice. These results suggest that a single, acute exercise bout reduces the capacity of splenic natural killer cells to kill tumor targets in vitro and that training enhances splenic natural killer cell cytolytic activity, on a per cell basis, against tumor targets.     

Human natural killer cell deficiencies and susceptibility to infection

There are a surprisingly large number of human natural killer (NK) cell deficiency states that provide insight into the role of NK cells in defense against human infectious disease. Many disorders associated with NK cell defects are caused by single gene mutations and, thus, give additional understanding concerning the function of specific molecules in NK cell development and activities. A resounding theme of NK cell deficiencies is susceptibility to herpesviruses, suggesting that unexplained severe herpesviral infection should raise the possibility of an NK cell deficit.     

Role of natural killer T lymphocytes during helminthic infection

Natural killer (NK)T cells are innate lymphocytes that release important amount of immunoregulatory cytokines (IFN-gamma and/or IL-4) shortly after T cell receptor engagement by (glyco)lipid antigens presented by the CD1d molecules. Through this property, NKT cells play pivotal role in many physiopathologic situations. Here, we review the current knowledge of the functions and mechanisms of activation of NKT cells during infection, with a particular emphasis on helminthic infections. Recent findings suggest that, although dispensable for host resistance, NKT cells play part in the development of the acquired immune response and in the control of the pathology during murine schistosomiasis.     

In vivo assessment of natural killer cell responses during chronic feline immunodeficiency virus infection

Accumulating evidence suggests that natural killer (NK) cells may have an important role in HIV-1 disease pathogenesis; however, in vivo studies are lacking. Feline immunodeficiency virus (FIV) infection of cats provides a valuable model to study NK cell function in vivo. The immune response against Listeria monocytogenes (Lm) is well characterized, allowing its use as an innate immune probe. We have previously shown that locally delivered IL-15 can improve Lm clearance in FIV-infected animals, and this correlated with an increase in NK cell number. In the present study, chronically FIV-infected and SPF-control cats were challenged with Lm by unilateral subcutaneous injection next to the footpad and then treated with 5-bromo-2'-deoxyuridine (BrdU). The Lm draining and contralateral control lymph nodes were evaluated for NK, NKT, CD4+ and CD8+ T cell number, proliferation, apoptosis, and NK cell function. Listeria monocytogenes burden was also assessed in both control and Lm draining lymph nodes. NK, NKT, CD4+ T and CD8+ T cells in the Lm-challenged lymph node of FIV-infected cats did not increase in number. In addition, after Lm challenge, NK cells from FIV-infected cats did not increase their proliferation rate, apoptosis was elevated, and perforin expression was not upregulated when compared to SPF-control cats. The failure of the NK cell response against Lm challenge in the draining lymph node of FIV-infected cats correlates with the delayed control and clearance of this opportunistic bacterial pathogen.     

NK细胞和NKT细胞发育的转录调控

自然杀伤（natural killer,NK）细胞和自然杀伤T（natural killer T,NKT）细胞是参与机体抗病毒免疫和肿瘤免疫的两群淋巴细胞亚群,是介导先天性免疫（innate immunity）应答和调节适应性免疫（adaptive immunity）应答的重要效应细胞。近年来,随着对NK细胞和NKT细胞及其转录调控因子研究的不断深入,NK细胞和NKT细胞的发育机制逐步被阐明,这将为提高NK细胞和NKT细胞的抗病毒和肿瘤免疫疗效提供新的策略。     

Structural and functional aspects of the Ly49 natural killer cell receptors

Natural killer cells are part of the first line of innate immune defence against virus-infected cells and cancer cells in the vertebrate immune system. They are called 'natural' killers because, unlike cytotoxic T cells, they do not require a previous challenge and preactivation to become active. The Ly49 NK receptors are type II transmembrane glycoproteins, structurally characterized as disulphide-linked homodimers. They share extensive homology with C-type lectins, and they are encoded by a multigene family that in mice maps on chromosome 6. A fine balance between inhibitory and activating signals regulates the function of NK cells. Inhibitory Ly49 molecules bind primarily MHC class I ligands, whereas the ligands for activating Ly49 molecules may include MHC class I, but also interestingly MHC class I-like molecules expressed by viruses, as is the case for Ly49H, which binds the m157 gene product of murine cytomegalovirus. In this study, we review the function and X-ray crystal structure of the Ly49 NK cell receptors hitherto determined (Ly49A, Ly49C and Ly49I), and the structural features of the Ly49/MHC class I interaction as revealed by the X-ray crystal structures of Ly49A/H-2Dd and the recently determined Ly49C/H-2Kb.     

自然杀伤细胞和自然杀伤T细胞在动脉粥样硬化形成中的作用

动脉粥样硬化发生发展与免疫细胞参与的免疫反应密切相关,其中自然杀伤细胞主要是通过释放IFN-γ、穿孔素和颗粒酶等方式发挥生物学作用,自然杀伤T细胞通过释放多种细胞因子影响动脉粥样硬化形成,但其具体机制未明。本文就自然杀伤细胞和自然杀伤T细胞对动脉粥样硬化的影响做一综述,为动脉粥样硬化及其相关疾病的防治研究提供新的思路。