A role for natural killer T cells in asthma

In several mouse models, natural killer T cells have recently been found to be required for the development of airway hyper-reactivity, a cardinal feature of asthma. Moreover, in patients with chronic asthma, natural killer T cells with a T-helper-2-like phenotype (that is, that express CD4 and produce T helper 2 cytokines) are present in the lungs in large numbers. In this Opinion article, we suggest that natural killer T cells, which express a restricted T-cell receptor and respond to glycolipids rather than protein antigens, have a previously unsuspected but crucial role, distinct from that of T helper 2 cells, in the pathogenesis of asthma.     

The role of natural killer cells in experimental murine salmonellosis

This study was designed to determine if murine natural killer (NK) cells play a role in host protection against a Salmonella typhimurium challenge infection. Outbred ICR mice injected intravenously with either attenuated (RIA strain) or virulent (SR-11 strain) salmonellae elicited enhanced killing of YAC-1 targets, which was maximal at 24 h after challenging. When NK cells were depleted with antiasialo GM1 prior to challenging, the splenic bacterial numbers were significantly less in this group of mice compared to sham-injected and challenged animals. The rabbit antiasialo GM1 sera had no detectable direct or indirect effect on the salmonellae. Our results indicate that the NK or natural suppressor cells may be functioning as down-regulators.     

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。     

Participatory role of natural killer and natural killer T cells in atherosclerosis: lessons learned from in vivo mouse studies

Atherosclerosis is a multifactor, highly complex disease with numerous aetiologies that work synergistically to promote lesion development. One of the emerging components that drive the development of both early- and late-stage atherosclerotic lesions is the participation of both the innate and acquired immune systems. In both humans and animal models of atherosclerosis, the most prominent cells that infiltrate evolving lesions are macrophages and T lymphocytes. The functional loss of either of these cell types reduces the extent of atherosclerosis in mice that were rendered susceptible to the disease by deficiency of either apolipoprotein E or the LDL (low density lipoprotein) receptor. In addition to these major immune cell participants, a number of less prominent leukocyte populations that can modulate the atherogenic process are also involved. This review will focus on the participatory role of two "less prominent" immune components, namely natural killer (NK) cells and natural killer T (NKT) cells. Although this review will highlight the fact that both NK and NKT cells are not sufficient for causing the disease, the roles played by both these cells types are becoming increasingly important in understanding the complexity of this disease process.     

The regulatory role of natural killer T cells in the airways

Asthma, an inflammatory disorder of the airways, has been considered a disease mediated by allergen-specific Th2 cells and eosinophils, and controlled by allergen-specific regulatory T cells. This paradigm can explain many but features of asthma, but Th2 targeted therapies in patients with asthma have not been as successful as might be predicted by this paradigm. These observations have suggested that other cell types, such as Natural Killer T cells, may play an important role in asthma. In this review, we discuss the data that support the notion that NKT cells critically regulate the development of asthma.     

The cytolytic and regulatory role of natural killer cells in experimental neoplasia

NK cells are defined here as cells, other than macrophages and polymorphonuclear leucocytes, from non-immunized animals (or humans) which are cytotoxic for neoplastic and non-neoplastic targets in the absence of specific antibody. Though not requiring antibody, they may function as K cells in ADCC. This definition includes cells activated nonspecifically by such agents as IFN and IL-2. Murine NK cells may be subdivided into two types by differences in the kinetics of target-cell lysis. Those we label Type 1 correspond roughly to what others have called NKA, NKL or simply NK cells; those of Type 2 to NKB, NKS and NC cells. Type 1 cells express various antigens, including NK-1, Thy-1 (50%), Ly-1 (25%), Qa-3, Qa-4, Qa-5, Ly-5, Ly-6, Ly-10, Ly-11 and asialo-GM1, not expressed by Type 2 cells, whereas Mac-1 may be expressed by both types. At least some NK cells appear to be pre-thymic cells which, in the presence of a thymus, can differentiate into T cells. The level of NK activity is influenced by the age and genetic background of the mouse, the organ from which the cells are obtained, and a variety of experimental manipulations. Type 1 activity is increased by IFN and IL-2; Type 2 activity by IL-3. IFN appears to be concerned in the development of spontaneous NK activity in young mice. Many experiments have shown that NK cells may inhibit the growth of tumours which are sensitive to NK cells of the same type in vitro. Inhibitory cells which suppress NK activity may play an important regulatory role in vivo. There is still uncertainty about how NK cells recognize their targets. Possibilities discussed are: (1) specific interacting molecules; (2) more diffuse properties of target cell membranes; (3) absence of MHC-coded self-recognition markers. Certainly, the presence of a Class 1 MHC molecule is not necessary. NK killing appears to be mediated by cytotoxins released by NK cells. In vivo, NK cells contribute to limiting the development of transplanted and primary tumours, and metastasis from established tumours. NK cells seem well qualified to act as a first-line defence against neoplasia, and may kill cells not killed by T cells. Transfer of NK cells may be of value in the treatment of cancer.     

An unusual presentation of fine needle aspiration (FNA) cytology from the syncytial variant of nodular sclerosing Hodgkin's disease

Introduction
Open access breast clinics are now widely available and immediate reporting of FNAs of the breast has become an established part of the triple approach to the management of breast disease ¹ .
We report the unexpected findings of a case of Hodgkin's disease at such a clinic. The patient was a young woman who initially was thought by both her general practitioner and surgeon to have a fibroadenoma in the axillary tail region of her right breast. The FNA of this lump showed the features of Hodgkin's disease but with widespread necrosis, which was unusual and potentially misleading and which we wish to highlight. A lymph node biopsy confirmed the diagnosis and showed that the patient was suffering from the syncytial variant of nodular sclerosing Hodgkin's disease (NSHD).
This variant probably accounts for about 5% of cases of Hodgkin's disease ² . Necrosis is a common feature of NSHD; it can range from minute scattered foci to more extensive necrosis of nodules or even involve the entire lymph node.     

Natural killer cells and natural killer T cells in Lyme arthritis

Introduction

Natural killer (NK) and natural killer T (NKT) cells provide a first line of defense against infection. However, these cells have not yet been examined in patients with Lyme arthritis, a late disease manifestation. Lyme arthritis usually resolves with antibiotic treatment. However, some patients have persistent arthritis after spirochetal killing, which may result from excessive inflammation, immune dysregulation and infection-induced autoimmunity.

Methods

We determined the frequencies and phenotypes of NK cells and invariant NKT (iNKT) cells in paired peripheral blood (PB) and synovial fluid (SF) samples from eight patients with antibiotic-responsive arthritis and fifteen patients with antibiotic-refractory arthritis using flow cytometry and cytokine analyses.

Results

In antibiotic-responsive patients, who were seen during active infection, high frequencies of CD56bright NK cells were found in SF, the inflammatory site, compared with PB (P <0.001); at both sites, a high percentage of cells expressed the activation receptor NKG2D and the chaperone CD94, a low percentage expressed inhibitory killer immunoglobulin-like receptors (KIR), and a high percentage produced IFN-γ. In antibiotic-refractory patients, who were usually evaluated near the conclusion of antibiotics when few if any live spirochetes remained, the phenotype of CD56bright cells in SF was similar to that in patients with antibiotic-responsive arthritis, but the frequency of these cells was significantly less (P = 0.05), and the frequencies of CD56dim NK cells tended to be higher. However, unlike typical NKdim cells, these cells produced large amounts of IFN-γ, suggesting that they were not serving a cytotoxic function. Lastly, iNKT cell frequencies in the SF of antibiotic-responsive patients were significantly greater compared with that of antibiotic-refractory patients where these cells were often absent (P = 0.003).

Conclusions

In patients with antibiotic-responsive arthritis, the high percentage of activated, IFN-γ-producing CD56bright NK cells in SF and the presence of iNKT cells suggest that these cells still have a role in spirochetal killing late in the illness. In patients with antibiotic-refractory arthritis, the frequencies of IFN-γ-producing CD56bright and CD56dim NK cells remained high in SF, even after spirochetal killing, suggesting that these cells contribute to excessive inflammation and immune dysregulation in joints, and iNKT cells, which may have immunomodulatory effects, were often absent.     

NKT细胞在抗肿瘤免疫中的作用及其机制

NKT细胞是免疫细胞中一类具有NK细胞特定标志的T细胞亚群,经活化,既可直接作为抗肿瘤效应细胞发挥杀伤作用,又能通过激活其他免疫效应细胞,如NK细胞,间接实现抗肿瘤作用。NKT细胞在抗肿瘤免疫、获得性免疫应答及免疫调节中起着重要作用。     

Natural killer and natural killer T cells in liver fibrosis

The liver lymphocyte population is enriched with natural killer (NK) cells, which play a key role in host defense against viral infection and tumor transformation. Recent evidence from animal models suggests that NK cells also play an important role in inhibiting liver fibrosis by selectively killing early or senescence activated hepatic stellate cells (HSCs) and by producing the anti-fibrotic cytokine IFN-γ. Furthermore, clinical studies have revealed that human NK cells can kill primary human HSCs and that the ability of NK cells from HCV patients to kill HSCs is enhanced and correlates inversely with the stages of liver fibrosis. IFN-α treatment enhances, while other factors (e.g., alcohol, TGF-β) attenuate, the cytotoxicity of NK cells against HSCs, thereby differentially regulating liver fibrogenesis. In addition, the mouse liver lymphocyte population is also enriched for natural killer T (NKT) cells, whereas human liver lymphocytes have a much lower percentage of NKT cells. Many studies suggest that NKT cells promote liver fibrogenesis by producing pro-fibrotic cytokines such as IL-4, IL-13, hedgehog ligands, and osteopontin; however, NKT cells may also attenuate liver fibrosis under certain conditions by killing HSCs and by producing IFN-γ. Finally, the potential for NK and NKT cells to be used as therapeutic targets for anti-fibrotic therapy is discussed. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.     

The role of monocytes and natural killer cells in mediating antibody-dependent lysis of colorectal tumour cells

Monocytes and natural killer (NK) cells are known to be important effector cell populations in mediating antibody-dependent cell-mediated cytotoxicity (ADCC). Purified monocyte and NK effector cell populations, from normal and colorectal cancer (CRC) patients, together with a number of murine (17-1A and 323/A3) and their chimaeric (c17-1A) or humanised (3622W94) equivalents, and chimaeric (c) SF25 were compared for their ability to mediate ADCC of colorectal tumour cells. The chimaeric and humanised antibodies were significantly better at mediating tumour lysis than their murine equivalents with all-effector populations. When effector cells from CRC patients were used the cSF25 antibody was significantly better than 3622W94 (P < 0.02) which, in turn, was significantly better than c17-1A (P < 0.03). Depletion of NK cells produced a decrease in specific tumour lysis with all antibodies. In addition a higher rate of NK cell death was observed in CRC patients during the assay than in normal controls. The chimaeric and humanised antibodies stained a similar percentage of the HT-29 target cells (>80%), but 3622W94 bound to significantly more cells from primary tumour biopsies than cSF-25 (P = 0.001). Together, the results suggest that NK cells are the most important effector cell type mediating ADCC in vitro, that there is some impairment of NK function in CRC patients, and that cSF25 is the most potent antibody. For use in vivo the anti-Ep-CAM antibody 3622W94 would appear to be the most suitable reagent for further study. Received: 3 June 1999 / Accepted: 22 July 1999     

Trafficking of natural killer cells

Natural killer (NK) cells comprise a set of lymphocytes that is capable of mediating innate immune responses to viral infections, malignancies, and allogeneic bone marrow grafts. This review summarizes what is known about the mechanisms NK cells use to arrive at their sites of action. NK cells express a wide array of adhesion molecules including alphaLbeta2, alphaMbeta2, alphaXbeta2, and alpha4beta1 integrins, ICAM-1, PSGL-1, and L-selectin. Like other immune and inflammatory cells, NK cells use the blood circulation to enter tissues and organs, which requires that they interact with the vessel wall under flow conditions, arrest, and transmigrate. NK cells are able to chemotax to a variety of cytokines and chemokines, including IL-12, IFN-(alpha/beta, CCL2, 3, 4, 5, 7, 8, CXCL8, and CX3CL1. In many cases, NK cells appear to migrate towards these soluble factors without any kind of priming. These cells also appear to distribute in secondary and tertiary lymphoid sites (i.e., spleen, bone marrow, liver, lung, and lymph nodes) both with and without stimulation. In addition to their ability to move throughout the body in an unprimed state, activated NK cells may have increased specificity in homing to sites of inflammation. NK cells not only react to, but also produce IFN-gamma, TNF-alpha, GM-CSF, CCL3, CCL4, and CCL5, enabling them to recruit various immune cells to sites of immune response.     

Self-tolerance of natural killer cells

Natural killer (NK) cells, similar to other lymphocytes, acquire tolerance to self. This means that NK cells have the potential to attack normal self cells but that there are mechanisms to ensure that this does not usually occur. Self-tolerance is acquired by NK cells during their development, but the underlying molecular and cellular mechanisms remain poorly understood. Recent studies have produced important new information about NK-cell self-tolerance. Here, we review the evidence for and against possible mechanisms of NK-cell self-tolerance, with an emphasis on the role of MHC-specific receptors.     

Renewal of natural killer cells in mice having elevated natural killer cell activity

The present study was designed to examined the dynamics of splenic natural killer (NK) cells under two conditions of enhanced NK cell activity: (1) CBA/J mice given polyinosinic-polycytidylic acid (poly-I:C), an NK-cell-enhancing agent, and 62) untreated athymic nude (nu/nu) mice. The 'total NK cell activity' of the spleen (percentage specific lysis corrected for changes in organ cellularity) increased 5-fold and 2.7-fold after poly-I:C treatment for 1 day and 4 days, respectively. An injection of hydroxyurea (HU), a cell-cycle-toxic drug, given together with either poly-I:C or saline to CBA/J mice resulted in both cases in a 25% reduction in total NK cell activity 1 day later. This suggests that the renewal rate of nondividing NK cells is similar in poly-I:C-treated and saline-injected mice, and that the NK-enhancing effect of poly-I:C is not due to a stimulation of proliferation among NK cell precursors. HU administered simultaneously with poly-I:C or saline for 4 days eliminated NK cell activity in both cases, indicating that spleen NK cell activity is mediated almost entirely by newly formed (less than or equal to 4 days) cells. In nude mice, NK cell activity was assayed at various intervals after an HU depletion period of 2 days. NK depletion was initially more rapid in nu/nu mice than in control (nu/+) mice, although equally profound, and the subsequent recovery of NK cell activity after cessation of HU was also more rapid than in control (nu/+) mice.(ABSTRACT TRUNCATED AT 250 WORDS)