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慢性乙型肝炎（CHB）是一世界性公共卫生问题。乙型肝炎病毒（HBV）持续性感染的关键是病毒复制环节中形成的闭合环状DNA,现有治疗措施难以将其彻底清除。研究表明,自然杀伤细胞（NK）在HBV慢性持续性感染过程中的表型和功能变化不同于急性感染,提示NK细胞的功能可能与机体能否清除HBV有关。NK细胞作为重要的天然免疫细胞,其发育、分化和活化依赖于代谢活性,哺乳动物雷帕霉素靶蛋白（m TOR）是一类与细胞代谢活性高度相关的丝氨酸/苏氨酸激酶,其磷酸化水平决定着NK细胞的代谢活性和功能。本文从HBV的慢性持续性感染、NK细胞的表型和功能、NK细胞发育分化与m TOR的关系等方面进行综述。

目的研究表达US3基因重组腺病毒载体对其转染肝细胞介导的免疫逃逸活性。方法首先构建表达US3基因腺病毒载体,扩增纯化后转染HL-7702肝细胞,利用细胞毒性T细胞（CTL）杀伤实验和自然杀伤细胞（NK）杀伤实验,检测表达US3基因重组腺病毒载体的免疫活性。结果表达US3基因的重组腺病毒r-US3成功构建,r-US3能够明显降低CTL和NK细胞对转染肝细胞的杀伤活性。结论表达US3基因腺病毒载体在一定程度上能够介导转染肝细胞的免疫逃逸,降低机体免疫系统对转染肝细胞的排斥反应。

目的探讨同种异体NK细胞杀伤人骨髓瘤ARH-77细胞的活性及机制。方法 LDH释放法检测NK细胞杀伤ARH-77细胞的活性;RT-PCR方法和流式细胞仪分别检测K562和ARH-77细胞NKG2D配体和HLA-I基因和分子。阻断K562和ARH-77细胞NKG2D配体,观察NK细胞杀伤活性的变化。结果相同效靶比时NK细胞杀伤ARH-77细胞的活性明显低于杀伤K562细胞。两种细胞均表达MICA/B和ULBP1～3基因。K562细胞高表达MICA/B和ULBP1～3分子,不表达HLA-Ⅰ类分子;ARH-77细胞低表达ULBP1～3分子,高表达HLA-Ⅰ类分子。ARH-77细胞HLA基因型为A2、3,B15、35,Cw3、4。阻断NKG2D配体,NK细胞对K562细胞的杀伤活性明显降低,对ARH-77细胞的杀伤活性无明显改变;阻断HLA-Ⅰ类分子后,NK细胞对K562细胞的杀伤活性无变化,对ARH-77细胞的杀伤活性明显提高。结论 ARH-77细胞对NK细胞的杀伤敏感性低,其机制与其高表达HLA-Ⅰ类分子、低表达NKG2D配体有关。

目的 研究白细胞介素-2（IL-2）和白细胞介素-18（IL-18）诱导自然杀伤（NK）细胞活化和抗骨髓瘤细胞活性的协同作用。方法 流式细胞仪方法检测NK细胞表面CD69的表达；阴性细胞纯化法用于获得高纯度的NK细胞；ELISA测定NK细胞培养上清液中干扰素（IFN-γ）的浓度；标准铬^51释放试验评估NK细胞杀伤骨髓瘤细胞的能力。结果 与单一应用IL-18相比，低浓度IL-2和IL-18联合应用显著提高了NK细胞的活性、分泌干扰素（IFN-γ）的水平和杀伤骨髓瘤细胞的作用。结论 低浓度IL-2具有协同IL-18活化NK细胞抗骨髓瘤细胞的作用，此结果为IL-2和IL-18联合应用治疗骨髓瘤奠定了一定的理论基础。

自然杀伤（natural killer,NK）细胞是先天性免疫效应细胞,约占人外周血淋巴细胞总数的10%-15%,主要参与免疫监视,以消除转化细胞和病毒感染细胞。NK细胞最初被界定是由于它们具有自发消除少数主要组织相容性复合物I类（major histocompatibility class I,MHC-I）自身分子表达缺乏细胞的能力,即常说的＂丢失自我＂识别能力。NK细胞表面表达的MHC-I特异性抑制性受体,可使NK细胞对表达MHC-I的正常细胞耐受,此为丢失自我识别能力的分子基础。由于缺乏抑制性受体的配体,表面MHC-I表达下调的肿瘤细胞和病毒感染细胞易受NK细胞攻击。杀伤细胞免疫球蛋白样受体（KIR;CD158）组成MHC-I结合受体家族,对调节人NK细胞和部分T细胞的活化阈值起重要作用。KIR多样性使NK细胞具有多种功能,在此我们将综述多个水平上的KIR多样性,并诠释KIR多样性是如何影响各种疾病（包括癌症）的易感性的。我们将进一步阐述通过针对KIR进行癌症治疗的策略：利用KIR/MHC-I配体的错配以强化造血干细胞移植的效果,以及通过阻滞KIR以增强对肿瘤细胞的杀伤力。

Natural killer （NK） cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells （iPSCs）, and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice （GMP） facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

Decidual natural killer （dNK） cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 （Tim-3） are expressed on over 60% of dNK cells. Tim-3^＋ dNK cells display higher interleukin （IL）-4 and lower tumor necrosis factor （TNF）-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 （Gal-9） and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide （LPS）-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper （Th）2-type cytokines were decreased and Thl-type cytokines were increased in Tim-3^＋ but not Tim-3- dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T （iNKT） cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice （CDld- and Ja18-deficient mice） were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone, iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines （e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin） involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CDld blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

Natural killer （NK） ceils are innate immune cells with the ability to identify and eliminate transformed cells. However, within tumors, many studies have described NK cells as non-functional. The developmental stage of tumor-associated NK cells and how this may relate to functionality has not been explored. We examined the developmental state of NK cells from polyoma middle T antigen （pyMT） transgenic mouse （MMTV-pMT） breast tumors. In pyMT tumors, NK cells were immature as evidenced by their decreased expression of DX5 and their CD27~~WCD1 lbI~w phenotype. These immature NK cells also had increased expression of NKG2A and expressed low levels of NKp46, perforin, and granzyme B. In contrast, splenic NK cells isolated from the same mice maintained their maturity and their expression of activation markers. To delineate whether the tumor microenvironment directly alters NK cells, we adoptively transferred labeled NK cells and followed their activation status in both the spleen and the tumor. NK cells that arrived at the tumor had half the expression of NKp46 within three days of transfer in comparison to those which arrived at the spleen. In an effort to modify the tumor microenvironment and assess the plasticity of intratumoral NK cells, we treated pyMT tumors with IL-12 and anti-TGF-β. After one week of treatment, the maturity of tumor-associated NK cells was increased; thus, indicating that these cells possess the ability to mature and become activated. A better understanding of how NK cells are modified by the tumor microenvironment will held to develop strategies aimed at bolstering immune resoonses against tumors.

MicroRNAs （miRNAs） are a class of small non-coding regulatory RNAs, and changes in miRNAs are involved in tumor origin and progression. Studies have shown that miR-20a is overexpressed in human ovarian cancer tissues and that this miRNA enhances long-term cellular proliferation and invasion capabilities. In this study, a positive correlation between serum miR-20a expression and ovarian cancer stage was observed. We found that miR-20a binds directly to the 3＇-untranslated region of MICA/B mRNA, resulting in its degradation and reducing its protein levels on the plasma membrane. Reduction of membrane-bound MICA/B proteins, which are ligands of the natural killer group 2 member D （NKG2D） receptor found on natural killer （NK） cells, y＋ T cells and CD8＋ T cells, allows tumor cells to evade immune-mediated killing. Notably, antagonizing miR-20a action enhanced the NKG2D-mediated killing of tumor cells in both in vitro and in vivo models of tumors. Taken together, our data indicate that increased levels of miR-20a in tumor cells may indirectly suppress NK cell cytotoxicity by downregulating MICA/B expression. These data provide a potential link between metastasis capability and immune escape of tumor cells from NK cells.