树突状细胞与自然杀伤细胞在免疫应答中的相互作用

树突状细胞(dendritic cells,DC)是专职的抗原提呈细胞,它们在免疫应答中发挥的作用越来越受到重视。NK细胞是固有免疫中的一种重要的效应细胞。当两者共培养后,在免疫应答中具有互惠作用。现就两者的生物学活性以及在免疫应答中相互作用的机制等方面作一综述。     

树突状细胞对自然杀伤细胞功能调控的研究进展

树突状细胞（DC）和自然杀伤细胞（NK）分别在固有免疫和适应性免疫中发挥着关键作用,二者之间还存在着复杂的交互作用.就DC对NK细胞功能的影响而言,前者可以通过膜表面分子直接激活静息的NK细胞,也可以在趋化因子的作用下将NK细胞招募至炎症部位或次级淋巴结,通过分泌可溶性细胞因子促进NK细胞活化、增殖,增强产生IFN-γ的能力,提高细胞毒活性,进而增强其抗病毒、抗肿瘤等效应.DC对NK细胞功能调控的研究在感染、肿瘤和免疫排斥等的防治中具有重要意义.     

HLA-C levels impact natural killer cell subset distribution and function

Differences in HLA-C expression are inversely correlated with HIV viral load set-point and slower progression to AIDS, linked to enhanced cytotoxic T cell immunity. Yet, beyond T cells, HLA-C serves as a dominant ligand for natural killer (NK) cell killer immunoglobulin-like receptors (KIR). Thus, we speculated that HLA-C expression levels may also impact NK activity, thereby modulating HIV antiviral control. Phenotypic and functional profiling was performed on freshly isolated PBMCs. HLA-C expression was linked to changes in NK subset distribution and licensing, particularly in HLA-C1/C1, KIR2DL3+2DL2-individuals. Moreover, high levels of HLA-C, were associated with reduced frequencies of anergic CD56^neg NKs and lower frequencies of KIR2DL1/2/3+ NK cells, pointing to an HLA-C induced influence on the NK cell development in the absence of disease. In HIV infection, several spontaneous controllers, that expressed higher levels of HLA-C demonstrated robust NK-IFN-γ secretion in response to target cells, highlighting a second disease induced licensing phenotype. Thus this population study points to a potential role for HLA-C levels both in NK cell education and development.     

自然杀伤细胞的基础研究和进展

人们对免疫系统的认识早已从单一的线性结构到充满着反馈性因素的网络结构,代表着固有免疫细胞的NK细胞是淋巴细胞中具有重要意义的第三类亚群.NK细胞具有特征性的功能包括杀伤病毒感染细胞或变异的肿瘤细胞,因而被称之为溶细胞性效应细胞,并且还有重要的分泌细胞因子和趋化因子功能,是固有免疫中重要的组成部分.     

Stromal-cell regulation of natural killer cell differentiation

Natural killer (NK) cells are bone-marrow-derived lymphocytes that play a crucial role in host defense against some viral and bacterial infections, as well as against tumors. Their phenotypic and functional maturation requires intimate interactions between the bone marrow stroma and committed precursors. In parallel to the identification of several phenotypic and functional stages of NK cell development, recent studies have shed new light on the role of stromal cells in driving functional maturation of NK cells. In this review, we provide an overview of the role of bone marrow microenvironment in NK cell differentiation.     

自然杀伤细胞的抗病毒活性

自然杀伤细胞是一类不同于T、B淋巴细胞的多功能淋巴细胞，在抗病毒免疫中发挥着重要作用。目前关于自然杀伤细胞参与抗病毒反应的研究主要集中于以下3点：①自然杀伤细胞介导抗病毒反应的路径；②自然杀伤细胞受体的功能；③自然杀伤细胞及自然杀伤T细胞在抗病毒反应中的激活和作用机理。尽管其中仍然存在许多悬而未决的问题，但大量的研究从分子水平揭示了自然杀伤细胞在病毒感染过程中的功能和反应。     

Suppression of murine natural killer cell activity by adherent cells from aging mice

Natural killer (NK) cell activity declines with age in mice. The purpose of this study was to investigate the effect of peritoneal and splenic adherent cells from young and old mice on NK activity to determine whether adherent cell suppressor function might contribute to this decline. Peritoneal adherent cells from old mice suppressed NK activity of young splenic non-adherent indicator cells more than peritoneal cells from young mice. Splenic adherent cells from old but not from young mice also suppressed this activity. That (1) the suppressive activity of the adherent cell populations was not affected by treatment with anti-Thy-1 plus complement, and that (2) the adherent cell population contained 77-92% cells positive for alpha-naphthyl acetate esterase activity, suggests that the active adherent suppressor cell may be a macrophage. Therefore, the age-related decline in NK activity in mice can be explained, in part, by an increase in adherent cell suppressor function.     

自然杀伤细胞表面受体NKp30的研究进展

自然杀伤(NK)细胞无需预先致敏即可快速杀伤靶细胞,是机体发挥抗肿瘤免疫和抗感染免疫的重要执行者.NK细胞的活化与否取决于细胞表面活化性受体和抑制性受体信号的平衡.NKp30是NK细胞表面的一种重要的活化性受体,可接收相应配体如BAG-6、B7-H6等分子信号进而激活NK细胞,发挥抗肿瘤和抗感染免疫作用.同时NKp30也是肿瘤细胞和病原体发生免疫逃逸的重要靶点,可通过多种机制逃逸NK细胞杀伤.此外,NKp30还参与了NK细胞和树突状细胞(DCs)间的双向免疫调节.     

Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection

Patients carrying activating killer cell immunoglobulin‐like receptor (KIR) genes are significantly protected from CMV‐associated complications after solid organ or hematopoietic stem cell transplantation. Whether previous infection with CMV affects NK‐cell function in healthy donors is unknown. We studied the KIR repertoire and alterations of KIR expression after in vitro exposure to CMV in 54 healthy donors. The expression of neither activating nor inhibitory KIRs was different at baseline between 23 seropositive and 31 seronegative donors. However, after co‐culture of NK cells with CMV‐infected fibroblast cells, expression of the inhibitory receptors KIR2DL1 and KIR2DL3 and the activating receptor KIR3DS1 significantly increased in CMV‐seropositive donors. In CMV‐seronegative donors, changes were subtle and restricted to the subset of NK cells expressing NK‐cell group antigen 2C (NKG2C). Expansion of inhibitory KIRs occurred exclusively in donors carrying the cognate HLA class I ligands, whereas the presence of the putative ligand HLA‐Bw4 was not necessary for the expansion of KIR3DS1‐expressing NK cells. Our data show that previous infection with CMV does not alter the resting NK‐cell receptor repertoire, but appears to modify how NK cells respond to re‐exposure to CMV in vitro.     

Vaccinia virus modulation of natural killer cell function by direct infection

Natural Killer (NK) cells have been implicated in the response to poxviruses, but the interaction between NK and infected cells is not well characterized. We show that downregulation of class I major histocompatibility complex (MHC-I) molecules in human cells by vaccinia virus (VV) sensitizes the cells to lysis by NK cells. We provide evidence suggesting that NK cells are infected as a consequence of co-culture with infected target cells. We also show that infection of NK cells leads to a marked depression of cytotoxicity. Moreover, the effect on NK cytotoxicity occurs within hours of infection and is prevented by UV inactivation of the virus but is only partially prevented by blocking late gene expression. VV infection also renders the NK cells more sensitive to inhibitory signals. Together our observations suggest that VV infection of NK cells can modulate their signaling in a manner that prevents them from acting on infected target cells.     

The biology of the human natural killer cell

Natural killer (NK) cells in the human are a population of large granular lymphocytes (LGL) with at least one unique surface antigen not expressed on cells of other lineages. NK-target-cell interaction appears to involve carbohydrate recognition and, following binding, the NK cells are induced to generate O₂ ^–, transmethylate membrane phospholipids, and activate phospholipase A₂. Some or all of these activities trigger a cascade of events which ultimately leads to the secretion of a substance toxic to the target cell. A variety of genes controls various steps in this cytolytic pathway. There is a good deal of evidence in the mouse, and some in the human, that NK cells play a role in host surveillance against tumor development, resistance to viral infections, and, possibly, hematopoietic regulation.     

Human newborns are deficient in natural killer activity

The peripheral blood natural killer (NK) activity of newborns was found to be significantly less than that of adults. In mixing experiments newborn cells inhibited adult NK activity in only one of nine instances. Interferon treatmentin vitro increased newborn NK activity to an even greater degree than adult NK activity. These findings imply that diminished newborn NK activity is due not to inhibitory cells or lack of pre-NK cells but rather to deficientin vivo activation of pre-NK cells. This deficiency may be a major factor in the increased susceptibility of newborns to certain virus infections.     

Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy

Chimeric antigen receptor (CAR)-engineered T-cell (CAR-T) therapy has demonstrated impressive therapeutic efficacy against hematological malignancies, but multiple challenges have hindered its application, particularly for the eradication of solid tumors. Innate killer cells (IKCs), particularly NK cells, NKT cells, and γδ T cells, employ specific antigen-independent innate tumor recognition and cytotoxic mechanisms that simultaneously display high antitumor efficacy and prevent tumor escape caused by antigen loss or modulation. IKCs are associated with a low risk of developing GVHD, thus offering new opportunities for allogeneic “off-the-shelf” cellular therapeutic products. The unique innate features, wide tumor recognition range, and potent antitumor functions of IKCs make them potentially excellent candidates for cancer immunotherapy, particularly serving as platforms for CAR development. In this review, we first provide a brief summary of the challenges hampering CAR-T-cell therapy applications and then discuss the latest CAR-NK-cell research, covering the advantages, applications, and clinical translation of CAR- and NK-cell receptor (NKR)-engineered IKCs. Advances in synthetic biology and the development of novel genetic engineering techniques, such as gene-editing and cellular reprogramming, will enable the further optimization of IKC-based anticancer therapies.     

Frequency and phenotype of natural killer cells and natural killer cell subsets in bovine lymphoid compartments and blood

Natural killer (NK) cells are widely distributed in lymphoid and non‐lymphoid tissues, but little is known about the recirculation of NK cells between blood and tissues. This is relevant to understanding recirculation in the steady‐state and also for determining the roles for NK cells in vaccine‐induced immunity and responses to infection. Therefore, the percentage of NK cells and their phenotype across peripheral blood, afferent lymph and lymph nodes in steady‐state conditions was investigated in cattle using the pseudo‐afferent lymphatic cannulation model. CD2⁺ CD25^lo NK cells were the predominant subset of NK cells within the blood. In contrast, CD2⁻ CD25^hi NK cells were the main subset present within the skin‐draining afferent lymphatic vessels and lymph nodes, indicating that CD2⁻ NK cells are the principal NK cell subset trafficking to lymph nodes via the afferent lymphatic vessel. Furthermore, a low percentage of NK cells were present in efferent lymph, which were predominantly of the CD2⁻ subset, indicating that NK cells can egress from lymph nodes and return to circulation in steady‐state conditions. These compartmentalization data indicate that NK cells represent a population of recirculating lymphocytes in steady‐state conditions and therefore may be important during immune responses to vaccination or infection.     

Human natural killer cell development in secondary lymphoid tissues

For nearly a decade it has been appreciated that critical steps in human natural killer (NK) cell development likely occur outside of the bone marrow and potentially necessitate distinct microenvironments within extramedullary tissues. The latter include the liver and gravid uterus as well as secondary lymphoid tissues such as tonsils and lymph nodes. For as yet unknown reasons these tissues are naturally enriched with NK cell developmental intermediates (NKDI) that span a maturation continuum starting from an oligopotent CD34⁺CD45RA⁺ hematopoietic precursor cell to a cytolytic mature NK cell. Indeed despite the detection of NKDI within the aforementioned tissues, relatively little is known about how, why, and when these tissues may be most suited to support NK cell maturation and how this process fits in with other components of the human immune system. With the discovery of other innate lymphoid subsets whose immunophenotypes overlap with those of NKDI, there is also need to revisit and potentially re-characterize the basic immunophenotypes of the stages of the human NK cell developmental pathway in vivo. In this review, we provide an overview of human NK cell development in secondary lymphoid tissues and discuss the many questions that remain to be answered in this exciting field.     

Dissociation of natural killer and lymphocyte-activated killer cell lytic activities in human CD3− large granular lymphocytes

CD3^? large granular lymphocytes (LGL) are known to display natural killer cell (NK) activity without prior sensitization or restriction by major histocompatibility antigens. Upon short-term exposure to interleukin-2, NK cells were shown to acquire lymphocyte-activated killer cell (LAK) activity. The aim of this study was to analyze the characteristics of these lytic activities. Our data indicated that both NK and LAK activities were Ca²⁺ dependent; however, they could be dissociated by a Ca²⁺ channel blocker or a Ca²⁺ channel competitor agent. Moreover, NK activity was associated with granule exocytosis of lytic proteins spontaneously present in CD3^? LGL, the most likely candidate being the pore-forming protein perforin. By contrast, LAK activity was found to be dependent on de novo protein synthesis and distinct from granule exocytosis. Our results strongly suggest that NK and LAK activities could be defined as two distinct pathways involving different lytic mediators.     

Angiocentric lymphoma with granulomatous panniculitis in the skin expressing natural killer cell and large granular T-cell phenotypes

We investigated three patients suffering from angiocentric lymphoma with granulomatous panniculitis in the skin. All three patients presented with multiple purple subcutaneous nodules. Immunohistologically, the lymphoma cells in all three patients expressed CD2 (T-11), CD56 (neural cell adhesion molecule), and Mik-1 (interleukin-2 receptor). CD3s (CD3, Leu-4)-positive lymphoma cells were found in two patients. A pore-forming protein (perforin) was detected in the lymphoma cells of all three patients. Perforin-possessing lymphoid cells were focally scattered in 2 of 15 patients with CD56-negative cutaneous lymphomas who served as controls. By the Southern blot method, one patient showed a rearranged T-cell receptor (TcR) gene in the biopsied specimen, and the other two patients had germline configurations of TcRs and immunoglobulin heavy chain genes. One patient had serum anti-human T-cell lymphotropic virus (HTLV)-I antibody, but showed no integration of its proviral DNA. Ultrastructurally, membrane-bound azurophilic granules were detected in the atypical lymphoid cells of all three patients. Angiocentric lymphoma with panniculitis in three patients showed the characteristics of natural killer and large granular T-cells. The histological features might be due to the characteristics of the neoplastic cells with azurophilic granules and perforin.This work was supported in part by Grants in Aid from the Fukuoka Cancer Society, Japan     

Age-related changes in natural killer cell receptors from childhood through old age

Most studies on natural killer (NK) cells and aging have focused on overall cell numbers and global cytotoxic activity. NK cell functions are controlled by surface receptors belonging to three major families: killer cell immunoglobulin-like receptors (KIRs), natural cytotoxicity receptors (NCRs), and C-type lectins. The expression of these receptors was investigated from childhood through old age in T, NKT- and NK cells and also in the CD56(dim) (cytotoxic) and CD56(bright) (responsible for cytokine production) NK cell subsets. A decrease in the expression of activating receptors (NKp30 and NKp46) was observed in NK cells in elderly individuals. KIR expression was increased only in the CD56(bright) subset. Children presented similar results regarding expression of NKp30 and KIR, but not NKp46. NKG2D expression was decreased in T cells of elderly subjects. Analysis of KIR genotype revealed that KIR2DL5 and KIR2DS3 were significantly associated with old age. Cytotoxic activity was preserved from childhood through old age, suggesting that the increase of the absolute number of CD56(dim), observed in elderly, may represent a compensatory mechanism for the receptor expression alterations. This initial study provides the framework for more focused studies of this subject, which are necessary to determine whether the changing balance of NK receptor expression may influence susceptibility to infectious, inflammatory, and neoplastic diseases.