NK 细胞负向调控适应性免疫应答研究进展

自然杀伤细胞(Natural killer cells,NK cells)是机体重要的天然免疫细胞,可以通过直接杀伤作用或分泌多种细胞因子来抵抗病毒感染或肿瘤细胞,从而维持机体稳态。大量研究表明,NK 细胞在免疫应答中也可以通过影响多种免疫细胞应答来改变免疫状态,一方面NK 细胞可以与免疫细胞直接接触,另一方面NK 细胞通过影响病毒载量等方式起到促进或抑制适应性免疫应答的作用。NK 细胞正向调控适应性免疫应答的功能已被人们所熟知,其负向调控功能直到近年才被关注。本文根据已有文献,综述了NK 细胞负向调控适应性免疫应答中的效应细胞及功能机制,并阐述这种调控作用对机体后续抗感染或抗肿瘤免疫应答的影响。     

半乳糖凝集素3对树突状细胞及T淋巴细胞功能影响的研究进展

半乳糖凝集素3(Gal-3)是半乳糖凝集素家族成员之一,它是半乳糖凝集素家族中唯一的嵌合型凝集素,存在于正常细胞和肿瘤细胞的胞核、胞质和细胞外基质中,能调节树突状细胞(DC)和T淋巴细胞的免疫功能,调节机体免疫应答和炎症反应。研究发现DC分泌Gal-3具有抑制自身凋亡、调节细胞因子生成以及调节T细胞应答等多种功能。同时Gal-3位于胞外和胞内对T淋巴细胞分别具有相反作用,胞外Gal-3诱导T细胞凋亡,胞内Gal-3抑制其凋亡。此外Gal-3在调节炎症反应中的起重要作用。     

自然流产妊娠期细胞因子失衡及治疗的干预

细胞因子是机体的免疫细胞和非免疫细胞合成和分泌的多肽类因子 ,调节多种细胞的生理功能 ,在机体的免疫应答、炎症反应、造血功能及生殖过程等各个方面都有作用。正常情况下 ,细胞因子表达和分泌受机体严格调控 ,在病理状态下 ,细胞因子会出现异常表达。正常妊娠中母体能耐受带有 1 2父方遗传基因的半同种异体胎儿 ,依赖免疫系统识别并产生保护性免疫应答 ,直至胎儿娩出。大量研究表明 :胎盘分泌的抑制因子及保护抗体、外周免疫无反应性、滋养层独特的主要组织相容性复合体 (MHC)表达 ,补体调节蛋白的表达、母胎界面复杂的激素网络和细胞…     

T-bet和Eomes对细胞免疫功能的调控作用

T-box expressed in T cells(T-bet)和Eomesodermin(Eomes)是调控I型效应T细胞的重要转录因子,对CD4I型辅助T细胞(Th1细胞)、NK细胞、CD8+细胞毒T淋巴细胞(CTL)等的分化发育和功能调控有重要作用。机体的抗肿瘤免疫主要依赖T淋巴细胞介导的适应性免疫应答和NK细胞介导的固有免疫应答。T-bet和Eomes通过调控这些免疫细胞影响抗肿瘤免疫应答,对肿瘤的发生、发展及转归有重要意义。     

肝脏驻留NK 细胞的发育分化及其个体发生

人和小鼠肝脏组织富含一群具有组织驻留特性的肝脏特有NK细胞,其与经典NK细胞在表型、功能、发育与分化等诸多方面具有显著差异。肝脏驻留NK细胞也被学界称为肝脏1型固有淋巴细胞,具有不成熟NK细胞的表型特征和很强的分泌细胞因子的能力,参与调节机体的免疫应答。肝脏驻留NK细胞与经典NK细胞受到不同转录因子的调控并呈现发育分化路径差异,在个体发生过程中的动态变化也不同。本文综述了肝脏驻留NK细胞的发现、发育分化、个体发生及微环境影响因素,为进一步对其深入研究提供新思路。     

NKT细胞在乙型病毒性肝炎治疗中作用的研究进展

自然杀伤性T细胞（NKT细胞）是一种同时具有自然杀伤细胞（NK细胞）和T细胞部分表型及功能的细胞亚群。它们能将固有免疫应答和适应性免疫应答连接起来，识别CDld-糖脂抗原，分泌细胞因子，参与调节机体的免疫应答。由于机体一些器官中（如肝脏）富含NKT细胞，因此NKT细胞在肝脏中的作用引起了人们的广泛兴趣。NKT细胞参与机体对乙型肝炎病毒的免疫应答，它们一方面抑制病毒复制，另一方面引起肝脏的免疫损伤，因而研究NKT细胞及其在乙型病毒性肝炎治疗中的作用可以对乙型病毒性肝炎的治疗提供新的思路。     

HLA-G调控自然杀伤细胞免疫功能的研究进展

人白细胞抗原G(HLA-G)属于非经典的HLAⅠ类分子,正常情况下主要表达于母胎界面绒毛外滋养层细胞。一些肿瘤细胞系、肿瘤组织、感染的组织细胞及正常组织细胞也可检测到HLA-G的表达。自然杀伤(NK)细胞是重要的固有免疫细胞,在免疫应答与免疫调节过程中发挥重要作用。HLA-G参与免疫调控引发了越来越多的关注,其功能由最初的"母胎耐受"逐渐扩展到肿瘤免疫逃逸、器官移植耐受等多个方面,本文重点回顾了HLA-G参与调控NK细胞免疫功能的各种机制:通过与受体相互作用抑制NK细胞的杀伤作用、调节NK细胞表面受体及细胞因子的表达、通过胞啃作用(trogocytosis)广泛引发免疫抑制、引发NK细胞凋亡。     

NK细胞发育分化分子机制及其相关疾病研究进展

自然杀伤细胞(Natural killer cells,NK细胞)是天然免疫应答中关键的效应细胞,通过分泌细胞因子和细胞杀伤功能发挥病原体清除和肿瘤免疫监视的作用。造血干细胞在外在因子和内在因子的调控下,可定向分化为NK细胞。经过30年的研究,科学家们在NK细胞发育过程、发育微环境、发育调控及NK细胞与疾病关系等基础和应用研究方面取得了长足进步。在本综述中,我们将详细探讨调控NK细胞发育的分子机制及NK细胞功能低下与疾病的关系。     

晚期肿瘤患者外周血CTL、Ts及NK细胞免疫表型的联检及临床意义

机体对肿瘤的免疫应答及其抗肿瘤免疫效应机理是肿瘤免疫学研究中的重要内容。细胞免疫在抗肿瘤免疫应答中发挥着重要作用。人类肿瘤特异性T细胞大多为CD8^＋T细胞,又可分为抑制性T细胞（Ts）和细胞毒性T细胞（CTL）,前者抑制体液和细胞免疫应答,调节维持内环境稳定,后者是直接杀伤肿瘤细胞的免疫效应细胞。NK细胞可溶解靶细胞如特异性肿瘤细胞株和受细胞内病原体感染的细胞,还可通过分泌炎性介质参与T细胞的分化,而控制T细胞反应。我们采用双色荧光标记流式细胞术分别检测了晚期肿瘤患者外周血CTL、Ts及NK细胞比例,从而评价晚期肿瘤患者的细胞免疫功能,对临床肿瘤治疗和预后判断具有重要的意义。     

NK细胞代谢途径及其功能

NK细胞是固有免疫系统的重要成员,在免疫应答中发挥关键作用。NK细胞激活主要依赖于其表面表达的活化性受体和抑制性受体间的动态平衡。然而,在许多慢性疾病模型中,NK细胞受体表达失衡,导致杀伤活性及细胞因子产生能力降低,处于免疫失活状态。近年许多研究表明,胞内代谢对包括NK细胞在内的免疫细胞至关重要,代谢改变能够通过影响细胞发育、增殖和活性等调节免疫细胞效应功能发挥。鉴于NK细胞强大的抗肿瘤和抗病毒功能及其重要的临床应用价值,深入研究其代谢特征及机制具有重要意义。本文主要从NK细胞的代谢方式及其相关调控通路、代谢对NK细胞发育、记忆和功能的调控作用以及基于代谢的NK细胞疗法进行综述,阐述代谢对NK细胞生物合成、体内稳定及效应功能的重要作用,以及不同慢性疾病模型中NK细胞失活的代谢相关因素,为NK细胞治疗的临床应用提供坚实的研究依据。     

The function of natural killer cells: education, reminders and some good memories

The effector response of natural killer (NK) cells is determined by opposing signals received through activating and inhibitory receptors. A process termed NK cell education, which is guided by the recognition of Major Histocompatibility Complex class I (MHC-I) molecules, determines how efficiently activating receptors respond to stimulation. This ensures NK cell tolerance to healthy tissues while allowing robust responses to diseased host cells. It was thought that NK cells are educated during their development in the bone marrow and that education fixes the NK cells' functional properties. However, recent findings suggest that the function of mature peripheral NK cells can adapt to changes in their environment and that the persistent exposure to normal-self is essential to maintain NK cell reactivity. Notwithstanding, NK cell stimulation in the context of inflammation can stably improve the functional properties of NK cells.     

Chemokines and NK cells: regulators of development, trafficking and functions

NK cells are innate lymphocytes capable of killing malignant or infected cells and to produce a wide array of cytokines and chemokines following activation. Chemokines, play critical roles in the regulation of NK cell tissue distribution in normal conditions as well as their rapid recruitment to the parenchyma of injured organs during inflammation, which is critical for NK cell ability to promote protective responses. In this regard, differences in chemokine receptor expression have been reported on specialized NK cell subsets with distinct effector functions and tissue distribution. Besides their role in the regulation of NK cell trafficking, chemotactic molecules can also affect NK cell effector functions by regulating their priming and their ability to kill and secrete cytokines.     

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.     

Natural killer cells and T cells induce different types of skin reactions during recall responses to haptens

The role of T cells in contact hypersensitivity (CHS) to haptens has been well described. However, recent reports demonstrated that CHS-like reactions to experimental haptens could be induced in mice deficient in T cells and B cells, as a result of adaptive-like features of NK cells. Here, we compared hapten-specific inflammatory reactions induced by memory T cells or NK cells. Classical CHS protocols were applied to WT or T- and B-cell deficient mice. Adoptive transfers of hapten-specific T cells and NK cells were also performed. Liver NK cells from hapten-primed mice induced specific recall responses to haptens upon transfer in CD3ε-deficient mice, thus confirming the existence of "memory" NK cells in the liver. We investigated the nature of the inflammation generated in these transfer conditions and found that hapten-induced skin inflammation mediated by CD8(+) T cells or "memory" NK cells are different. Indeed, ear swelling induced by memory NK cells was transient and not associated with cellular infiltrate and inflammation markers, characteristic for T-cell-mediated responses. Thus, NK cells and T cells mediate distinct forms of skin inflammation. NK cell-mediated pathogenesis does not rely on cellular infiltrate and could be involved in atypical forms of adverse drug reactions.     

Subsets of human natural killer cells and their regulatory effects

Human natural killer (NK) cells have distinct functions as NK^tolerant, NK^cytotoxic and NK^regulatory cells and can be divided into different subsets based on the relative expression of the surface markers CD27 and CD11b. CD27⁺ NK cells, which are abundant cytokine producers, are numerically in the minority in human peripheral blood but constitute the large population of NK cells in cord blood, spleen, tonsil and decidua tissues. Recent data suggest that these NK cells may have immunoregulatory properties under certain conditions. In this review, we will focus on these new NK cell subsets and discuss how regulatory NK cells may serve as rheostats or sentinels in controlling inflammation and maintaining immune homeostasis in various organs.     

Compartmentalization of human natural killer cells

Human natural killer (NK) cells are bone marrow-derived cells that are found in the bloodstream, but can extravasate into various tissue sites upon inflammation. NK cells that migrate toward inflamed sites must be activated prior to their extravasation. However, the factors responsible for NK cell compartmentalization are not clearly defined. Resting human NK cells (CD16(-) and CD16(+)) express constitutive chemokine receptors, as well as receptors that have both constitutive and inflammatory functions. Upon activation, NK cells up-regulate the expression of the inflammatory chemokine receptors which facilitate their distribution into inflammatory sites. However, chemokines are not expected to play any role in maintaining resting NK cells in the blood circulation. In contrast, members of the lysolipids which are abundant in the bloodstream may be the major factors responsible for maintaining resting NK cells in the bloodstream, and also for facilitating their extravasation into inflamed tissues. Both resting and activated NK cells express receptors for various lysolipids. Hence, chemoattractants which include chemokines and lysolipids have important roles in determining the compartmentalization of NK cells where resting NK cells are found in the blood circulation, and activated NK cells extravasate into inflamed sites.     

Activating and inhibitory receptors on synovial fluid natural killer cells of arthritis patients: role of CD94/NKG2A in control of cytokine secretion

Natural killer (NK) cells are activated early during inflammatory events and contribute to the shaping of the ensuing adaptive immune response. To further understand the role for NK cells in inflammation, we investigated the phenotype and function of synovial fluid (SF) NK cells from patients with chronic joint inflammation, as well as from patients with transient inflammation of the knee following trauma. We confirm that synovial NK cells are similar to the well-characterized CD56(bright) peripheral blood (PB) NK-cell subset present in healthy individuals. However, compared to this PB subset the synovial NK cells express a higher degree of activation markers including CD69 and NKp44, the latter being up-regulated also on CD56(bright) NK cells in the PB of patients. Activated synovial NK cells produced interferon-gamma and tumour necrosis factor, and the production was further up-regulated by antibody masking of CD94/NKG2A, and down-regulated by target cells expressing human leucocyte antigen-E in complex with peptides known to engage CD94/NKG2A. We conclude that synovial NK cells have an activated phenotype and that CD94/NKG2A is a key regulator of synovial NK-cell cytokine synthesis.     

Balance between activating NKG2D,DNAM‐1, NKp44 and NKp46 and inhibitory CD94/NKG2A receptors determine natural killer degranulation towards rheumatoid arthritis synovial fibroblasts

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and synovial hyperplasia leading to progressive joint destruction. Fibroblast‐like synoviocytes (FLS) are central components of the aggressive, tumour‐like synovial structure termed pannus, which invades the joint space and cartilage. A distinct natural killer (NK) cell subset expressing the inhibitory CD94/NKG2A receptor is present in RA synovial fluid. Little is known about possible cellular interactions between RA‐FLS and NK cells. We used cultured RA‐FLS and the human NK cell line Nishi, of which the latter expresses an NK receptor repertoire similar to that of NK cells in RA synovial fluid, as an in vitro model system of RA‐FLS/NK cell cross‐talk. We show that RA‐FLS express numerous ligands for both activating and inhibitory NK cell receptors, and stimulate degranulation of Nishi cells. We found that NKG2D, DNAM‐1, NKp46 and NKp44 are the key activating receptors involved in Nishi cell degranulation towards RA‐FLS. Moreover, blockade of the interaction between CD94/NKG2A and its ligand HLA‐E expressed on RA‐FLS further enhanced Nishi cell degranulation in co‐culture with RA‐FLS. Using cultured RA‐FLS and the human NK cell line Nishi as an in vitro model system of RA‐FLS/NK cell cross‐talk, our results suggest that cell‐mediated cytotoxicity of RA‐FLS may be one mechanism by which NK cells influence local joint inflammation in RA.     

Immunostimulatory DNA mediates inhibition of eosinophilic inflammation and airway hyperreactivity independent of natural killer cells in vivo.

BACKGROUND: Immunostimulatory DNA sequences (ISS) inhibit eosinophilic inflammation and airway hyperreactivity in mouse models of asthma. In vitro ISS activate natural killer (NK) cells to secrete IFN-gamma, and this cytokine is hypothesized to contribute to the antiallergic effect of ISS in vivo. OBJECTIVE: We investigated whether ISS activation of NK cells is important in mediating the reduction in airway hyperreactivity and the antieosinophilic effect of ISS in vivo. METHODS: We assessed whether ISS modulated the development of eosinophilic airway inflammation and airway hyperreactivity to methacholine in ovalbumin (OVA)-sensitized and OVA allergen-challenged mice pretreated with an antibody to deplete NK cells. RESULTS: Mice sensitized and challenged with OVA had significant bronchoalveolar lavage and lung eosinophilia, as well as airway hyperresponsiveness. ISS induced significant inhibition of bronchoalveolar lavage and lung eosinophilia, as well as airway hyperresponsiveness, in OVA-sensitized mice pretreated before OVA challenge with an NK cell-depleting antibody (NK(-) mice), as well as in mice pretreated with a control non-NK cell-depleting antibody (NK(+) mice). The NK cell-depleting antibody inhibited ISS-induced IFN-gamma production by spleen cells. CONCLUSION: These studies demonstrate that depletion of NK cells has no significant effect on ISS-mediated inhibition of airway eosinophilia and airway hyperresponsiveness in vivo, suggesting that non-NK cells and cytokines other than IFN-gamma derived from NK cells mediate the majority of the ISS-inhibitory effect on eosinophilic inflammation and airway hyperresponsiveness in vivo.