Differential modulating effect of natural killer (NK) T cells on interferon-γ production and cytotoxic function of NK cells and its relationship with NK subsets in Chlamydia muridarum infection

Natural killer T (NKT) cells are a newly identified T-cell population with potential immunomodulatory functions. Several studies have shown modulating effects of NKT cells activated by α-galactosylceramide, a model antigen, on NK cell function. We here report a differential modulating effect of NKT cells on the interferon-γ (IFN-γ) production and cytolytic function of NK cells in a chlamydial infection model, using NKT-cell-deficient mice and antibody blocking (anti-CD1d monoclonal antibody) approaches. Our results showed that both NKT and NK cells became activated and produced IFN-γ following Chlamydia muridarum infection in vitro and in vivo. The NK cells in NKT-cell-deficient mice and CD1d-blocked mice showed decreased CD69 expression, cellular expansion and IFN-γ production but surprisingly showed increased cytolytic activity (degranulation) of immature and more mature NK cell subsets, suggesting an inhibitory role of NKT cells on NK cell killing activity. The results suggest that NKT cells preferentially promote IFN-γ production but are inhibitory for the cytotoxic function of NK cells in this infection model. Furthermore, the differential modulating effect of NKT cells on the IFN-γ production and cytotoxicity of NK cells was observed in immature and mature NK cell subsets, although it was more dramatic in the relatively mature CD11b(high) CD27(high) NK cell subset. This finding demonstrates the complexity of innate cell interactions in infection and the possible differential impact of NKT cells on the variable functional aspects of other cell(s) even in one infection setting.     

Tolerance and reactivity of NK cells: Two sides of the same coin?

NK cells can kill transformed, infected and stressed cells while most normal cells are spared. NK cells are activated by various endogenous self-ligands, some of which are actually expressed by normal cells. Thus, NK cells are inherently self-reactive and consequently, potentially auto-aggressive. How these cells are prevented from attacking normal cells while ensuring reactivity to diseased cells is a major unresolved question for NK-cell biologists.     

Recycling and reutilization of cytotoxic molecules,a new type of energy conservation of NK cells?

Natural killer (NK) cells play critical roles in defense against tumors and viral infections. They exert their cytotoxic functions through the secretion of granules containing cytotoxic molecules, such as perforin and granzymes. These cytotoxic molecules are stored within dual-functional organelles, known as secretory lysosomes. Target cell recognition induces the formation of an "immunological synapse", between the NK cell and its target, into which cytotoxic granules release their contents. However the post-exocytosis regulation of the process is still largely unknown. Recent research and the data accumulated therefrom lead to new hypotheses that suggest that, not unlike synaptic vesicle recycling in neuronal terminals, NK cells also recycle not just their secretory lysosome membranes but their correlated cytotoxic molecules (perforin and granzymes). The newly endocytosed vesicles are used to replenish the "reserve pool" of vesicles for continued NK cell serial killings. These hypotheses, if proved to be correct, will significantly improve our understanding of NK cell cytotoxicity mechanisms and might even suggest new NK cell-based therapies that rely on NK serial killing abilities for overcoming tumors.     

The double life of NK receptors: stimulation or co-stimulation?

Stimulatory killer immunoglobulin-like receptors, NKG2D and stimulatory receptors of the CD94-NKG2 family have duplicity in function. On natural killer (NK) cells, these receptors act as independent and competent recognition units. Stimulatory NK receptors also appear on subsets of effector T cells, particularly those that have replicated extensively. When expressed on T cells, they amplify signals mediated through the T-cell antigen receptor and, thus, function as co-stimulatory, but not direct stimulatory, molecules. One mechanism responsible for this dichotomy is the differential expression of adaptor molecules. This duplicity in function, which is not seen for other co-stimulatory molecules, is responsible for the unique context information provided by the NK receptors, and it could explain their involvement in chronic inflammation and autoimmunity.     

Interferon-γ-secreting NK cells promote induction of dry eye disease

NK cells have been increasingly reported to be an important effector in autoimmune diseases. However, nothing is known in this regard in DED, the most common eye pathology, which is characterized by sustained inflammation on the ocular surface. In the present study, we have examined the profile of NK cells on the ocular surface as well as in the draining lymphoid tissues during the development of this disease. Our data demonstrate activated NK cells during the disease-induction phase. Moreover, in vivo depletion of NK cells in mice results in reduced disease severity and diminished proinflammatory cytokines. Furthermore, we show that NK cells are also able to modulate the maturation of APCs, which is correlated with IFN-γ from NK cells. Together, our findings provide new in vivo evidence that IFN-γ-secreting NK cells can promote induction of DED via direct target tissue damage and indirect influence on the priming phase of an adaptive immune response in secondary lymphoid tissue.     

NK T细胞

NKT细胞 (NaturalKillerTcell ,自然杀伤T细胞 )是在鼠和人中发现的独特的T细胞群。它们除了表达T细胞的标志外 ,也能表达NK细胞的一些标志。NKT细胞的活化具有CD1限制性。它们通过产生细胞因子IL 4 /IFN γ的作用而成为先天性免疫和获得性免疫中发挥关键作用的一类调节性细胞 ,且为抗感染的第一线防御功能的一部分。本文拟就有关方面作一综述     

The immunoregulatory effects of NK cells: the role of TGF-β and implications for autoimmunity

The cytotoxic activities of natural killer (NK) cells — important in innate immunity — have received considerable attention, but NK cells also regulate T- and B-cell functions as well as hematopoiesis. Here, David Horwitz and colleagues focus on the capacity of NK cells to regulate antibody production positively and negatively, and in particular on the role of NK-cell transforming growth factor β (TCF-β) in downregulation of B-cell activity.     

Impaired IFN-γ production and proliferation of NK cells in multiple sclerosis

NK cells are multicompetent lymphocytes of the innate immune system with a central role in host defense and immune regulation. Studies in experimental animal models of multiple sclerosis (MS) provided evidence for both pathologic and protective effects of NK cells. Humans harbor two functionally distinct NK-cell subsets exerting either predominantly cytotoxic (CD56(dim)CD16(+)) or immunoregulatory (CD56(bright)CD16(-)) functions. We analyzed these two subsets and their functions in the peripheral blood of untreated patients with relapsing-remitting MS compared with healthy blood donors. While ex vivo frequencies of CD56(bright)CD16(-) and CD56(dim)CD16(+) NK cells were similar in patients and controls, we found that cytokine-driven in vitro accumulation and IFN-γ production of CD56(bright)CD16(-) NK cells but not of their CD56(dim)CD16(+) counterparts were substantially diminished in MS. Impaired expansion of CD56(bright)CD16(-) NK cells was cell intrinsic because the observed effects could be reproduced with purified NK cells in an independent cohort of patients and controls. In contrast, cytolytic NK-cell activity toward the human erythromyeloblastoid leukemia cell line K562, the allogeneic CD4(+) T cell line CEM and allogeneic primary CD4(+) T-cell blasts was unchanged. Thus, characteristic functions of CD56(bright)CD16(-) NK cells, namely cytokine-induced NK cell expansion and IFN-γ production, are compromised in the NK cell compartment of MS patients.     

HLA-G与NK细胞

自然杀伤细胞(natural killer,NK)是天然免疫系统的主要效应细胞,是机体抵抗肿瘤和病毒感染的第一道防线。人类白细胞抗原-G(human leukocyte antigen-G,HLA-G)属于非经典的HLAⅠ类分子,是机体内一个重要的免疫耐受分子。HLA-G抗原对NK细胞的免疫调节功能一方面是依赖于一系列杀伤细胞免疫球蛋白样受体,另一方面是通过调节NK细胞多种趋化因子受体表达。本文就HLA-G对NK细胞调节功能的研究进展作一综述。     

调节NK的因素

NK细胞是免疫系统的重要组成部分,除细胞毒活性外,它也具有免疫调节作用,一些因素也影响NK细胞的功能.LGL细胞有相当强的分泌功能,能产生种种细胞因子,包括白细胞介素1(IL-1)及2(IL-2)、α及γ干扰素、克隆刺激因子(CSF)以及B细胞生长因子(BCGF).因此,LGL可能是重要的免疫调节细胞,它能通过所产生的细胞因子影响免疫系统种     

Early Reconstitution of NK and γδ T Cells and Its Implication for the Design of Post-Transplant Immunotherapy

Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Natural killer (NK) cells and γδ T cells reconstitute early after allo-HSCT, contribute to tumor immunosurveillance via major histocompatibility complex–independent mechanisms and do not induce graft-versus-host disease. Here we performed a quantitative and qualitative analysis of the NK and γδ T cell repertoire in healthy individuals, recipients of HLA-matched sibling or unrelated donor allo-HSCT (MSD/MUD-HSCT) and umbilical cord blood-HSCT (UCB-HSCT). NK cells are present at high frequencies in all allo-HSCT recipients. Immune reconstitution (IR) of vδ2⁺?cells depended on stem cell source. In MSD/MUD-HSCT recipients, vδ2⁺?comprise up to 8% of the total lymphocyte pool, whereas vδ2⁺?T cells are barely detectable in UCB-HSCT recipients. Vδ1⁺?IR was driven by CMV reactivation and was comparable between MSD/MUD-HSCT and UCB-HSCT. Strategies to augment NK cell mediated tumor responses, similar to IL-15 and antibodies, also induced vδ2⁺?T cell responses against a variety of different tumor targets. Vδ1⁺?γδ T cells were induced less by these same stimuli. We also identified elevated expression of the checkpoint inhibitory molecule TIGIT (T cell Ig and ITIM domain), which is also observed on tumor-infiltrating lymphocytes and epidermal γδ T cells. Collectively, these data show multiple strategies that can result in a synergized NK and γδ T cell antitumor response. In the light of recent developments of low-toxicity allo-HSCT platforms, these interventions may contribute to the prevention of early relapse.     

NK细胞的研究

自1960年Govaerts证明体内致敏的淋巴细胞在体外对相应的靶细胞有细胞毒性作用后,近年来又发现正常哺乳类动物(包括小鼠、大鼠、豚鼠、田鼠),和正常人的淋巴细胞,在体外能杀伤某些靶细胞,使之溶解。靶细胞可以是自体、同系、同     

NK细胞受体研究进展

NK细胞受体是自然杀伤细胞功能发挥的分子基础 ,NK细胞抑制性及激活性受体的分子结构及其特异性配体是目前研究的热点。本文综述了该领域的最新进展     

NK细胞受体研究进展

NK细胞受体是自然杀伤细胞功能发挥的分子基础，NK细胞抑制性及激活性受体的分子结构及其特异性配体是目前研究的热点。本文综述了该领域的最新进展。     

NK细胞研究新进展

本文总结了近年来NK 细胞研究的新进展;在分子、基因水平上概述了NK 的来源,NK 原始细胞、前体细胞的表型,促进NK 细胞成熟的细胞因子,NK 细胞的走向,NK 细胞多分子相互作用,NK 细胞可能具有的受体,NK 细胞参与的同种识别及其耐受状态和NK 识别中MHC Ⅰ类抗原分子抗原结合深糟状构型的调节作用等。     

肿瘤细胞的NK抵抗性

NK细胞通过识别某些目前尚不清楚的肿瘤细胞的“靶结构”杀伤破坏肿瘤细胞,对肿瘤的发生发展有明确的控制作用,是免疫监视功能的主要组成部分。众所周知,机体NK细胞功能不足时,肿瘤便逃避免疫监视,得以生存和发展;而很少了解的另一方面,即肿瘤细胞自身的“适应性调变”所致     

NK细胞的形态学

十多年来,一些学者研究了人及动物NK细胞的性质.越来越多的迹象表明NK细胞有多种功能:包括对肿瘤,对病毒、对其他微生物感染、对骨髓移植的天然抵抗力.现就NK细胞的形态学、NK与K细胞的关系、NK细胞的细胞毒机理、NK细胞的调节作用、NK细胞与肿瘤及感染等的关系分别加以讨论.一、NK细胞的特征Santoli等(1979)从单个核细胞组分中除去粘附的及吞噬细胞,发现增强了细胞毒活性,并发现细胞毒组分富含于带有IgGFc受体的细胞而不含于具有IgMFc受     

NK细胞与肿瘤

一些实验证据表明,NK细胞在抵抗肿瘤中占有重要地位,以下就近年来NK细胞在抗肿瘤中的研究概况加以讨论.一、NK细胞抗肿瘤作用在对鼠的研究中观察到,体外NK活性高与体内对瘤形成的抵抗力之间呈正相关;注射富含NK细胞的淋巴细胞群体能延缓体内肿瘤的生长.由种种肿瘤的实验表明,肿瘤生长遗传抵抗力的一个主要机     

Anti-tumor activity of patient-derived NK cells after cell-based immunotherapy – a case report

Background  

Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. A phase I clinical trial has shown that repeated re-infusions of ex vivo TKD/IL-2-activated, autologous leukapheresis product is safe. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2-activated effector cells.