KIR基因表达调控机制及其对NK细胞功能的影响
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摘要
背景和目的:自然杀伤(natural killer,NK)细胞属于人体固有免疫系统,是机体抵御病毒感染和肿瘤的第一道重要防线。杀伤细胞免疫球蛋白样受体(killer cell immnoglobulin-like receptors,KIRs)是表达在人NK细胞表面、具有多态性的分子家族。人NK细胞对靶细胞的识别主要依赖于KIRs对靶细胞表面的人白细胞抗原(human leukocyte antigen,HLA)I类分子的监视。不同KIR可以传递抑制性或激活性信号,两者之间的平衡状态决定了NK细胞杀伤靶细胞的效应功能。抑制性KIRs不仅对肿瘤和病毒感染发挥免疫监视作用,而且在区分正常和异常细胞的免疫耐受中同样发挥重要作用。因此,明确抑制性KIR因表达调控机制及其与NK细胞功能的联系有助于在体内、外调控NK细胞。本研究分析了DNA甲基化和转录因子E2F对KIR基因表达的调控作用,并观察了去甲基化处理对NK细胞杀伤活力的影响。
方法:(1)为分析KIR3DL1基因启动子甲基化模式及其与基因表达的关系,采用亚硫酸氢盐测序法检测表达KIR3DL1的人NK细胞系NK-92MI和不表达KIR3DL1的人白血病细胞系K562中KIR3DL1启动子区CpG岛甲基化模式,然后应用甲基化抑制剂5-氮胞苷(5-azacytidine,5-Aza)处理NK-92MI细胞以诱导CpG岛去甲基化,RT-PCR检测KIR3DL1基因表达水平。为明确转录因子E2F在调控KIR3DL1启动子转录活性中的作用,采用PCR分别从K562细胞基因组DNA和含有野生型KIR3DL1启动子序列的质粒中扩增突变型和野生型KIR3DL1基因核心启动子序列,产物分别连接入pGL3-Basic荧光素酶载体构建报告重组质粒;采用染色质免疫共沉淀(chromatin immunoprecipitation,CHIP)方法检测E2F1与KIR3DL1启动子在细胞内的结合;采用阳离子脂质体SuperFect包裹突变型和野生型KIR3DL1启动子-荧光素酶报告重组质粒转染K562细胞,CHIP方法检测E2F1与重组质粒在细胞内的结合,双荧光素酶检测试剂盒测定荧光素酶活性;最后,将E2F1真核表达载体与KIR3DL1启动子-荧光素酶报告重组质粒共转染K562细胞,双荧光素酶检测试剂盒测定荧光素酶活性。(2)为明确DNA去甲基化对NK细胞杀伤功能的直接影响及机制,采用亚硫酸氢盐测序法检测NK-92MI细胞中抑制性KIR基因启动子区甲基化模式,RT-PCR和流式细胞仪检测5-Aza处理前后的NK细胞抑制性KIR基因表达水平;采用5-Aza分别处理NK-92MI细胞和新鲜分离的人外周血NK细胞,并采用流式细胞仪将NK细胞群分选为KIR3DL1阳性和KIR3DL1阴性细胞亚群,采用乳酸脱氢酶释放法检测NK细胞对K562细胞的杀伤活力;采用酶联免疫吸附试验检测NK细胞释放粒酶B和穿孔素的水平。
结果:(1)NK-92MI和K562细胞中,KIR3DL1基因核心启动子区存在高甲基化,采用5-Aza处理能够诱导NK-92MI和K562细胞KIR3DL1基因表达水平增加。测序证实,在K562细胞中,KIR3DL1启动子区一个潜在的转录因子E2F结合位点上有一个自然发生的点突变(TT(?)GGCGC→TT(?)GGCGC),这一突变引入了一个新的被甲基化的CpG二核苷酸位点;E2F1能与NK-92MI细胞中野生型KIR3DL1启动子结合,上述结合位点的突变使它们在K562细胞中的结合完全丧失;突变型KIR3DL1启动子-荧光素酶报告重组质粒保留了部分与E2F1的结合能力;突变型KIR3DL1启动子的相对荧光素酶活性较野生型降低了50%;共转染E2F1表达载体使野生型KIR3DL1启动子的相对荧光素酶活性较对照组增加了2.4倍。(2)NK-92MI细胞中抑制性KIR基因(KIR2DL1、KIR2DL2、KIR2DL3和KIR3DL1)由于启动子区存在高甲基化而呈现特征性的表达抑制状态,5-Aza处理可以诱导这些抑制性KIR基因表达增加;经5-Aza处理的NK-92MI细胞和新鲜分离的人外周血NK细胞对K562细胞的杀伤活力则明显受到抑制,此外,NK细胞释放粒酶B和穿孔素的水平也明显降低;在5-Aza处理后的NK细胞群中,KIR3DL1阴性细胞亚群的杀伤活力、释放粒酶B和穿孔素的水平均高于KIR3DL1阳性细胞亚群。
结论:NK细胞KIR3DL1基因表达受启动子甲基化调控。转录因子E2F1参与调控KIR3DL1基因转录激活。去甲基化处理抑制NK细胞的杀伤活力,该作用可能与去甲基化处理诱导的抑制性KIR基因过表达及细胞毒性颗粒释放减少有关。
Background and aims:Natural killer(NK) cells as a component of the innate immune system provide a first line of defense against viral infections and malignancies.Killer immunoglobulin-like receptors(KIRs) are a polymorphic gene family expressed on NK cells.In humans,a major component of NK cell target recognition depends mainly on the surveillance of human leukocyte antigen (HLA) classⅠmolecules by KIRs.Different KIR can transmit inhibitory or activating signal to the cell,and effector function is considered to result from the balance of these contributing signals.Inhibitory KIRs are important not only for tumor and virus-infection surveillance,but also for immunological tolerance to discriminate between normal and abnormal cells.Clarifying the relationship between inhibitory KIRs regulation and NK cell function will facilitate the potential manipulation of these immunocytes both in vitro and in vivo.In this study,we investigated the regulation of DNA methylation and transcription factor E2F on KIR gene expression and analyzed the direct effect of DNA demethylating treatment on human NK cell cytolytic activity.
Methods:(1) To analyze the promoter methylation patterns of KIR3DL1 gene and its relationship with gene expression,the CpG methylation pattern of KIR3DL1 promoter region in KIR3DL1-positive human NK cell line NK-92MI and KIR3DL1-negative human leukemic cell line K562 was detected by bisulfite sequencing technique.Then NK-92MI cells were treated with 5-azacytidine (5-Aza) to induce the demethylation of CpG islands.The level of KIR3DL1 gene expression was determined by RT-PCR.To study the role of transcription factor E2F in the transcriptional activity of KIR3DL1 promoter,the mutant and wild-type core promoter fragment of KIR3DL1 gene was respectively amplified from K562 genomic DNA and a plasmid containing the wild-type KIR3DL1 promoter sequence by PCR.PCR products were cloned into pGL3-basic reporter vector to construct KIR3DL1 promoter-luciferase reporter plasmids.The binding of E2F1 to KIR3DL1 promoter was detected by chromatin immunoprecipitation (CHIP) assay.KIR3DL1 promoter-luciferase reporter construct was transfected into K562 cells using polycationic compound SuperFect.The binding of E2F1 to the construct was detected by CHIP assay and reporter activity was quantitated using the dual-luciferase reporter assay system.Finally,the mammalian expression vector containing E2F1 cDNA was co-transfected into K562 cells with KIR3DL1 promoter-luciferase reporter construct and reporter activity was quantitated using the dual-luciferase reporter assay system.(2) To investigate the direct effect of DNA demethylating treatment on human NK cell cytolytic activity, NK-92MI cells and freshly isolated human primary NK cells were respectively treated with 5-Aza.The KIR3DL1-positive and -negative NK cell subsets were sorted by flow cytometry.The cytotoxicity of NK cells against human K562 leukemic cells was detected by the lactate dehydrogenase release assay.The promoter methylation patterns of inhibitory KIR genes in NK-92MI cell line were detected by bisulfite sequencing technique.The levels of inhibitory KIRs expression in 5-Aza-treated and untreated NK cells were determined by RT-PCR and flow cytometry.The granzyme B and perforin release by NK cells was detected by enzyme linked immunosorbent assay.
Results:(1) The core promoter region of KIR3DL1 gene exhibits densely methylated in NK-92MI and K562 cells.Treatment of NK-92MI and K562 cells with 5-Aza significantly increased the expression level of KIR3DL1 gene.DNA sequencing revealed a naturally occurring point mutation(TT(?)GGCGC→TT(?)GGCGC) within a putative E2F binding site in the KIR3DL1 promoter in K562 cells.Interestingly,this mutation introduced a new methylation site.E2F1 could bind to the KIR3DL1 promoter in NK-92MI cells,and the point mutation in the E2F binding site absolutely abolished their binding in K562 cells.The binding of E2F1 to the mutant KIR3DL1 promoter-reporter construct was partially abolished compared to its binding to the wild-type construct.The mutation in E2F binding site significantly decreased the relative luciferase activity of the mutant construct,yielding an average of 50%of activity of the wild-type one. Co-transfection of E2F1 expression plasmid transactivated the wild-type KIR3DL1 promoter,yielding about 2.4-fold higher values than the non-cotransfected control.(2) Inhibitory KIR genes including KIR2DL1, KIR2DL2,KIR2DL3 and KIR3DL1 exhibited characteristic epigenetic repression,whose promoter regions are densely methylated.Treatment of NK-92MI cells with 5-Aza significantly increased the expression levels of these inhibitory KIRs.But the cytolytic activity of NK-92MI cells and freshly isolated human NK cells against human K562 leukemic cells was strongly suppressed upon 5-Aza-treatment.Furthermore,granzyme B and perforin release by NKs cells was also decreased.Among the 5-Aza-treated NK cells,both cytolytic activity and level of granzyme B and perforin release in KIR3DL1-negative NK subsets were higher than those in KIR3DL1-positive ones.
Conclusion:The KIR3DL1 gene expression in NK cells is determined by promoter methylation.E2F1 contributes to the transcriptional activation of the KIR3DL1 gene.Demethylating treatment suppresses NK cell cytolytic activity. The suppression is associated with 5-Aza-induced overexpression of inhibitory KIRs and impaired cytotoxic granules release by these cells.
方法:(1)为分析KIR3DL1基因启动子甲基化模式及其与基因表达的关系,采用亚硫酸氢盐测序法检测表达KIR3DL1的人NK细胞系NK-92MI和不表达KIR3DL1的人白血病细胞系K562中KIR3DL1启动子区CpG岛甲基化模式,然后应用甲基化抑制剂5-氮胞苷(5-azacytidine,5-Aza)处理NK-92MI细胞以诱导CpG岛去甲基化,RT-PCR检测KIR3DL1基因表达水平。为明确转录因子E2F在调控KIR3DL1启动子转录活性中的作用,采用PCR分别从K562细胞基因组DNA和含有野生型KIR3DL1启动子序列的质粒中扩增突变型和野生型KIR3DL1基因核心启动子序列,产物分别连接入pGL3-Basic荧光素酶载体构建报告重组质粒;采用染色质免疫共沉淀(chromatin immunoprecipitation,CHIP)方法检测E2F1与KIR3DL1启动子在细胞内的结合;采用阳离子脂质体SuperFect包裹突变型和野生型KIR3DL1启动子-荧光素酶报告重组质粒转染K562细胞,CHIP方法检测E2F1与重组质粒在细胞内的结合,双荧光素酶检测试剂盒测定荧光素酶活性;最后,将E2F1真核表达载体与KIR3DL1启动子-荧光素酶报告重组质粒共转染K562细胞,双荧光素酶检测试剂盒测定荧光素酶活性。(2)为明确DNA去甲基化对NK细胞杀伤功能的直接影响及机制,采用亚硫酸氢盐测序法检测NK-92MI细胞中抑制性KIR基因启动子区甲基化模式,RT-PCR和流式细胞仪检测5-Aza处理前后的NK细胞抑制性KIR基因表达水平;采用5-Aza分别处理NK-92MI细胞和新鲜分离的人外周血NK细胞,并采用流式细胞仪将NK细胞群分选为KIR3DL1阳性和KIR3DL1阴性细胞亚群,采用乳酸脱氢酶释放法检测NK细胞对K562细胞的杀伤活力;采用酶联免疫吸附试验检测NK细胞释放粒酶B和穿孔素的水平。
结果:(1)NK-92MI和K562细胞中,KIR3DL1基因核心启动子区存在高甲基化,采用5-Aza处理能够诱导NK-92MI和K562细胞KIR3DL1基因表达水平增加。测序证实,在K562细胞中,KIR3DL1启动子区一个潜在的转录因子E2F结合位点上有一个自然发生的点突变(TT(?)GGCGC→TT(?)GGCGC),这一突变引入了一个新的被甲基化的CpG二核苷酸位点;E2F1能与NK-92MI细胞中野生型KIR3DL1启动子结合,上述结合位点的突变使它们在K562细胞中的结合完全丧失;突变型KIR3DL1启动子-荧光素酶报告重组质粒保留了部分与E2F1的结合能力;突变型KIR3DL1启动子的相对荧光素酶活性较野生型降低了50%;共转染E2F1表达载体使野生型KIR3DL1启动子的相对荧光素酶活性较对照组增加了2.4倍。(2)NK-92MI细胞中抑制性KIR基因(KIR2DL1、KIR2DL2、KIR2DL3和KIR3DL1)由于启动子区存在高甲基化而呈现特征性的表达抑制状态,5-Aza处理可以诱导这些抑制性KIR基因表达增加;经5-Aza处理的NK-92MI细胞和新鲜分离的人外周血NK细胞对K562细胞的杀伤活力则明显受到抑制,此外,NK细胞释放粒酶B和穿孔素的水平也明显降低;在5-Aza处理后的NK细胞群中,KIR3DL1阴性细胞亚群的杀伤活力、释放粒酶B和穿孔素的水平均高于KIR3DL1阳性细胞亚群。
结论:NK细胞KIR3DL1基因表达受启动子甲基化调控。转录因子E2F1参与调控KIR3DL1基因转录激活。去甲基化处理抑制NK细胞的杀伤活力,该作用可能与去甲基化处理诱导的抑制性KIR基因过表达及细胞毒性颗粒释放减少有关。
Background and aims:Natural killer(NK) cells as a component of the innate immune system provide a first line of defense against viral infections and malignancies.Killer immunoglobulin-like receptors(KIRs) are a polymorphic gene family expressed on NK cells.In humans,a major component of NK cell target recognition depends mainly on the surveillance of human leukocyte antigen (HLA) classⅠmolecules by KIRs.Different KIR can transmit inhibitory or activating signal to the cell,and effector function is considered to result from the balance of these contributing signals.Inhibitory KIRs are important not only for tumor and virus-infection surveillance,but also for immunological tolerance to discriminate between normal and abnormal cells.Clarifying the relationship between inhibitory KIRs regulation and NK cell function will facilitate the potential manipulation of these immunocytes both in vitro and in vivo.In this study,we investigated the regulation of DNA methylation and transcription factor E2F on KIR gene expression and analyzed the direct effect of DNA demethylating treatment on human NK cell cytolytic activity.
Methods:(1) To analyze the promoter methylation patterns of KIR3DL1 gene and its relationship with gene expression,the CpG methylation pattern of KIR3DL1 promoter region in KIR3DL1-positive human NK cell line NK-92MI and KIR3DL1-negative human leukemic cell line K562 was detected by bisulfite sequencing technique.Then NK-92MI cells were treated with 5-azacytidine (5-Aza) to induce the demethylation of CpG islands.The level of KIR3DL1 gene expression was determined by RT-PCR.To study the role of transcription factor E2F in the transcriptional activity of KIR3DL1 promoter,the mutant and wild-type core promoter fragment of KIR3DL1 gene was respectively amplified from K562 genomic DNA and a plasmid containing the wild-type KIR3DL1 promoter sequence by PCR.PCR products were cloned into pGL3-basic reporter vector to construct KIR3DL1 promoter-luciferase reporter plasmids.The binding of E2F1 to KIR3DL1 promoter was detected by chromatin immunoprecipitation (CHIP) assay.KIR3DL1 promoter-luciferase reporter construct was transfected into K562 cells using polycationic compound SuperFect.The binding of E2F1 to the construct was detected by CHIP assay and reporter activity was quantitated using the dual-luciferase reporter assay system.Finally,the mammalian expression vector containing E2F1 cDNA was co-transfected into K562 cells with KIR3DL1 promoter-luciferase reporter construct and reporter activity was quantitated using the dual-luciferase reporter assay system.(2) To investigate the direct effect of DNA demethylating treatment on human NK cell cytolytic activity, NK-92MI cells and freshly isolated human primary NK cells were respectively treated with 5-Aza.The KIR3DL1-positive and -negative NK cell subsets were sorted by flow cytometry.The cytotoxicity of NK cells against human K562 leukemic cells was detected by the lactate dehydrogenase release assay.The promoter methylation patterns of inhibitory KIR genes in NK-92MI cell line were detected by bisulfite sequencing technique.The levels of inhibitory KIRs expression in 5-Aza-treated and untreated NK cells were determined by RT-PCR and flow cytometry.The granzyme B and perforin release by NK cells was detected by enzyme linked immunosorbent assay.
Results:(1) The core promoter region of KIR3DL1 gene exhibits densely methylated in NK-92MI and K562 cells.Treatment of NK-92MI and K562 cells with 5-Aza significantly increased the expression level of KIR3DL1 gene.DNA sequencing revealed a naturally occurring point mutation(TT(?)GGCGC→TT(?)GGCGC) within a putative E2F binding site in the KIR3DL1 promoter in K562 cells.Interestingly,this mutation introduced a new methylation site.E2F1 could bind to the KIR3DL1 promoter in NK-92MI cells,and the point mutation in the E2F binding site absolutely abolished their binding in K562 cells.The binding of E2F1 to the mutant KIR3DL1 promoter-reporter construct was partially abolished compared to its binding to the wild-type construct.The mutation in E2F binding site significantly decreased the relative luciferase activity of the mutant construct,yielding an average of 50%of activity of the wild-type one. Co-transfection of E2F1 expression plasmid transactivated the wild-type KIR3DL1 promoter,yielding about 2.4-fold higher values than the non-cotransfected control.(2) Inhibitory KIR genes including KIR2DL1, KIR2DL2,KIR2DL3 and KIR3DL1 exhibited characteristic epigenetic repression,whose promoter regions are densely methylated.Treatment of NK-92MI cells with 5-Aza significantly increased the expression levels of these inhibitory KIRs.But the cytolytic activity of NK-92MI cells and freshly isolated human NK cells against human K562 leukemic cells was strongly suppressed upon 5-Aza-treatment.Furthermore,granzyme B and perforin release by NKs cells was also decreased.Among the 5-Aza-treated NK cells,both cytolytic activity and level of granzyme B and perforin release in KIR3DL1-negative NK subsets were higher than those in KIR3DL1-positive ones.
Conclusion:The KIR3DL1 gene expression in NK cells is determined by promoter methylation.E2F1 contributes to the transcriptional activation of the KIR3DL1 gene.Demethylating treatment suppresses NK cell cytolytic activity. The suppression is associated with 5-Aza-induced overexpression of inhibitory KIRs and impaired cytotoxic granules release by these cells.
引文
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24 Stewart CA,van Bergen J,Trowsdale J.Different and divergent regulation of the KIR2DL4 and KIR3DL1 promoters.J Immunol,2003,170(12):6073-6081.
25 王长青,肖强,李雷,谢玉波,谭宁,宫志伟.E2F-1基因真核表达载体的构建及其对胃癌细胞株 MKN-45增殖的影响.癌症,2007,26(10):1064-1068.
26 Frommer M,McDonald LE,Millar DS,Collis CM,Watt F,Grigg GW,Molloy PL,Paul CL.A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands.Proc Nati Acad Sci USA,1992,89(5):1827-1831.
27 Thompson A,van der Slik AR,Koning F,van Bergen J.An improved RT-PCR method for the detection of killer-cell immunoglobulin-like receptor (kir) transcripts.Immunogenetics,2006,58(11):865-872.
28 van Bergen J,Stewart CA,van den Elsen PJ,Trowsdale J.Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptors.Eur J Immunol,2005,35(7):2191-2199.
29 Teixeira LA,Fricke CH,Bonorino CB,Bogo MR,Nardi NB.An efficient gene transfer system for hematopoietic cell line using transient and stable vectors.J Biotechnol,2001,88(2):159-165.
30 Lavrrar JL,Farnham PJ.The use of transient chromatin immunoprecipitation assays to test models for E2F1-specific transcriptional activation.J Biol Chem,2004,279(44):46343-46349.
31 Santourlidis S,Trompeter HI,Weinhold S,Eisermann B,Meyer KL,Wernet P,Uhrberg M.Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells.J Immunol,2002,169(8):4253-4261.
32 Gardiner-Garden M,Frommer M.CpG islands in vertebrate genomes.Mol Biol,1987,196(2):261-282.
33 Rius M,Stresemann C,Keller D,Brom M,Schirrmacher E,Keppler D,Lyko F.Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation.Mol Cancer Ther,2009,8(1):225-231.
34 Campanero MR,Armstrong MI,Flemington EK.CpG methylation as a mechanism for the regulation of E2F activity.Proc Nat Acad Sci USA,2000,97(12):6481-6486.
35 Cerwenka A,Lanier LL.Natural killer cells,viruses and cancer.Nat Rev Immunol,2001,1(1):41-49.
36 Vivier E,Tomasello E,Baratin M,Walzer T,Ugolini S.Functions of natural killer cells.Nat Immunol,2008,9(5):503-510.
37 Kelley J,Walter L,Trowsdale J.Comparative genomics of natural killer cell receptor gene clusters.PloS Genet,2005,1(2):129-139.
38 Santourlidis S,Graffmann N,Christ J,Uhrberg M.Lineage-specific transition of histone signatures in the killer cell Ig-like receptor locus from hematopoietic progenitor to NK cells.J Immunol,2008,180(1):418-425.
39 Chan HW,Kurago ZB,Stewart CA,Wilson MJ,Martin MP,Mace BE,Carrington M,Trowsdale J,Lutz CT.DNA methylation maintains allele-specific KIR gene expression in human natural killer cells.J Exp Med,2003,197(2):245-255.
40 Chan HW,Miller JS,Moore MB,Lutz CT.Epigenetic control of highly homologous killer Ig-like receptor gene alleles.J Immunol,2005,175(9):5966-5974.
41 Trundley A,Frebel H,Jones D,Chang C,Trowsdale J.Allelic expression patterns of KIR3DS1 and 3DL1 using the Z27 and DX9 antibodies.Eur J Immunol,2007,37(3):780-787.
42 Smyth MJ,Cretney E,Kelly JM,Westwood JA,Street SE,Yagita H,Takeda K,van Dommelen SL,Degli-Esposti MA,Hayakawa Y.Activation of NK cell cytotoxicity.Mol Immunol,2005,42(4):501-510.
43 Salcedo TW,Azzoni L,Wolf SF,Perussia B.Modulation of perforin and granzyme messenger RNA expression in human natural killer cells.J Immunol,1993,151(5):2511-2520.
44 DeBlaker-Hohe DF,Yamauchi A,Yu CR,Horvath-Arcidiacono JA,Bloom ET.IL-12 synergizes with IL-2 to induce lymphokine-activated cytotoxicity and perforin and granzyme gene expression in fresh human NK cells.Cell Immunol,1995,165(1):33-43.
45 Attwood JT,Yung RL,Richardson BC.DNA methylation and the regulation of gene transcription.Cell Mol Life Sci,2002,59(2):241-257.
46 Bruniquel D,Schwartz RH.Selective,stable demethylation of the interleukin-2 gene enhances transcription by an active process.Nat Immunol,2003,4(3):235-240.
47 Floess S,Freyer J,Siewert C,Baron U,Olek S,Polansky J,Schlawe K,Chang HD,Bopp T,Schmitt E,Klein-Hessling S,Serfling E,Hamann A,Huehn J.Epigenetic control of the foxp3 locus in regulatory T cells.PLoS Biol,2007,5(2):e38.
48 Hershkovitz O,Zilka A,Bar-Ilan A,Abutbul S,Davidson A,Mazzon M,K(u|¨)mmerer BM,Monsoengo A,Jacobs M,Porgador A.Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells.J Virol,2008,82(15):7666-7676.
49 Johnson DR.Differential expression of human major histocompatibility class I loci:HLA-A,-B,and-C.Hum Immunol,2000,61(4):389-396.
50 Reiter Z,Reiter Y,Fishelson Z,Shinitzky M,Kessler A,Loyter A,Nussbaum O,Rubinstein M.Resistance to NK cell-mediated cytotoxicity(in K-562 cells)does not correlate with class I MHC antigen levels.Immunobiology,1991,183(12):23-39.
51 Cooper MD.Inhibition of immune cell function.Immunol Rev,2008,224:7-10.
52 Trapani JA,Smyth MJ.Functional significance of the perforin/granzyme cell death pathway.Nat Rev Immunol,2002,2(10):735-747.
53 Heusel JW,Wesselschmidt RL,Shresta S,Russell JH,Ley TJ.Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells.Cell,1994,76(6): 977-987.
54 Shi L,Kam CM,Powers JC,Aebersold R,Greenberg AH.Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions.J Exp Med,1992,176(6):1521-1529.
55 Kagi D,Ledermann B,Biirki K,Seiler P,Odermatt B,Olsen KJ,Podack ER,Zinkernagel RM,Hengartner H.Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice.Nature,1994,369(6475):31-37.
56 Anfossi N,Andre P,Guia S,Falk CS,Roetynck S,Stewart CA,Breso V,Frassati C,Reviron D,Middleton D,Romagne F,Ugolini S,Vivier E.Human NK cell education by inhibitory receptors for MHC class I.Immunity,2006,25(2):331-342.
57 Perricone R,Perricone C,De Carolis C,Shoenfeld Y.NK cells in autoimmunity:A two-edg'd weapon of the immune system.Autoimmun Rev,2008,7(5):384-390.
58 Boyton RJ,Altmann DM.Natural killer cells,killer immunoglobulin-like receptors and human leucocyte antigen class I in disease.Clin Exp Immunol,2007,149(1):1-8.
1 Parham P.MHC class Ⅰ molecules and KIRs in human history,health and survival.Nat Rev Immunol,2005,5(3):201-214.
2 Marsh SG,Parham P,Dupont B,Geraghty DE,Trowsdale J,Middleton D,Vilches C,Carrington M,Witt C,Guethlein LA,Shilling H,Garcia CA,Hsu KC,Wain H.Killer-cell immunoglobulin-like receptor(KIR) nomenclature report,2002.Eur J Immunogenet,2003,30(3):229-234.
3 Vilches C,Parham P.KIR:diverse,rapidly evolving receptors of innate and adaptive immunity.Annu Rev Immunol,2002,20:217-251.
4 Maxwell LD,Wallace A,Middleton D,Curran MD.A common KIR2DS4deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey.Tissue Antigens,2002,60(3):254-258.
5 Long EO.Tumor cell recognation by natural killer cells.Semin Cancer Biol,2002,12(1):57-61.
6 Hsu KC,Chida S,Geraghty DE,Dupont B.The killer cell immunoglobulin-like receptor(KIR) genomic region:gene-order,haplotypes and allelic polymorphism.Immunol Rev,2002,190:40-52.
7 Yawata M,Yawata N,Draghi M,Little AM,Partheniou F,Parham P.Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function.J Exp Med,2006,203(3):633-645.
8 Young NT.Immunobiology of Natural Killer Lymphocytes in Transplantation.Transplantation,2004,78(1):1-6.
9 Watzl C,Long EO.Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4(CD244)to lipid rafts.J Exp Med,2003,197(1):77-85.
10 Miller JS,McCullar V.Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2.Blood,2001,98(3):705-713.
11 Belkin D,Torkar M,Chang C,Barten R,Tolaini M,Haude A,Allen R,Wilson MJ,Kioussis D,Trowsdale J.Killer cell Ig-like receptor and leukocyte Ig-like receptor transgenic mice exhibit tissue-and cell-specific transgene expression.J Immunol,2003,171(6):3056-3063.
12 Doucey MA,Scarpellino L,Zimmer J,Guillaume P,Luescher IF,Bron C,Held W.Cis association of Ly49A with MHC class I restricts natural killer cell inhibition.Nat Immunol,2004,5(3):328-336.
13 Shilling HG,Young N,Guethlein LA,Cheng NW,Gardiner CM,Tyan D,Parham P.Genetic control of human NK cell repertoire.J Immunol,2002(1),169:239-247.
14 van Bergen J,Stewart CA,van den Elsen PJ,Trowsdale J.Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptors.Eur J Immunol,2005,35(7):2191-2199.
15 Trompeter HI,Gomez-Lozano N,Santourlidis S,Eisermann B,Wernet P,Vilches C,Uhrberg M.Three Structurally and Functionally Divergent Kinds of Promoters Regulate Expression of Clonally Distributed Killer Cell Ig-Like Receptors(KIR),of KIR2DL4,and of KIR3DL3.J Immunol,2005,174(7):4135-4143.
16 Chan HW,Kurago ZB,Stewart CA,Wilson MJ,Martin MP,Mace BE,Carrington M,Trowsdale J,Lutz CT.DNA methylation maintains allele-specific KIR gene expression in human natural killer cells.J Exp Med,2003,197(2):245-255.
17 Santourlidis S,Trompeter HI,Weinhold S,Eisermann B,Meyer KL,Wernet P, Uhrberg M.Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells.J Immunol,2002,169(8):4253-4261.
18 Rouhi A,Gagnier L,Takei F,Mager DL.Evidence for epigenetic maintenance of Ly49a monoallelic gene expression.J Immunol,2006,176(5):2991-2999.
19 Turner BM.Cellular memory and the histone code.Cell,2002,111(3):285-291.
20 Chan HW,Miller JS,Moore MB,Lutz CT.Epigenetic control of highly homologous killer Ig-like receptor gene alleles.J Immunol,2005,175(9):5966-5974.
2 Moretta L,Bottino C,Pende D,Vitale M,Mingari MC,Moretta A.Human natural killer cells:molecular mechanisms controlling NK cell activation and tumor cell lysis.Immunol Lett,2005,100(1):7-13.
3 Trinchieri G.Biology of natural killer cells.Adv Immunol,1989,47:187-376.
4 Verheyden S,Demanet C.NK cell receptors and their ligands in leukemia.Leukemia,2008,22(2):249-257.
5 Nakajima H,Zhao R,Lund TC,Ward J,Dolan M,Hirsch B,Miller JS.The BCR/ABL transgene causes abnormal NK cell differentiation and can be found in circulating NK cells of advanced phase chronic myelogenous leukemia patients.J Immunol,2002,168(2):643-650.
6 Costello RT,Sivori S,Marcenaro E,Lafage-Pochitaloff M,Mozziconacci MJ,Reviron D,Gastaut JA,Pende D,Olive D,Moretta A.Defective expression and function of natural killer cell triggering receptors in patients with acute myeloid leukemia.Blood,2002,99(10):3661-3667.
7 Siegler U,Kalberer CP,Nowbakht P,Sendelov S,Meyer-Monard S,Wodnar-Filipowicz A.Activated natural killer cells from patients with acute myeloid leukemia are cytotoxic against autologous leukemic blasts in NOD/SCID mice.Leukemia,2005,19(12):2215-2222.
8 Kiladjian JJ,Bourgeois E,Lobe I,Braun T,Visentin G,Bourhis JH,Fenaux P,Chouaib S,Caignard A.Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes.Leukemia,2006,20(3):463-470.
9 Epling-Burnette PK,Bai F,Painter JS,Rollison DE,Salih HR,Krusch M,Zou J,Ku E,Zhong B,Boulware D,Moscinski L,Wei S,Djeu JY,List AF.Reduced natural killer(NK)function associated with high-risk myelodysplastic syndrome(MDS)and reduced expression of activating NK receptors.Blood,2007,109(11):4816-4824.
10 Demanet C,Mulder A,Deneys V,Worsham MJ,Maes P,Claas FH,Ferrone S.Down-regulation of HLA-A and HLA-Bw6,but not HLA-Bw4,allospecificities in leukemic cells:an escape mechanism from CTL and NK attack? Blood,2004,103(8):3122-3130.
11 Brouwer RE,van der Heiden P,Schreuder GM,Mulder A,Datema G,Anholts JD,Willemze R,Claas FH,Falkenburg JH.Loss or downregulation of HLA class I expression at the allelic level in acute leukemia is infrequent but functionally relevant,and can be restored by interferon.Hum Immunol,2002,63(3):200-210.
12 Ruggeri L,Mancusi A,Capanni M,Urbani E,Carotti A,Aloisi T,Stern M,Pende D,Perruccio K,Burchielli E,Topini F,Bianchi E,Aversa F,Martelli MF,Velardi A.Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia:challenging its predictive value.Blood,2007,110(1):433-440.
13 Ruggeri L,Mancusi A,Burchielli E,Aversa F,Martelli MF,Velardi A.Natural killer cell alloreactivity in allogeneic hematopoietic transplantation.Curr Opin Oncol,2007,19(2):142-147.
14 Bethge WA,Haegele M,Faul C,Lang P,Schumm M,Bornhauser M,Handgretinger R,Kanz L.Haploidentical allogeneic hematopoietic cell transplantation in adults with reduced-intensity conditioning and CD3/CD19 depletion:fast engraftment and low toxicity.Exp Hematol,2006,34(12):1746-1752.
15 Ruggeri L,Mancusi A,Burchielli E,Perruccio K,Aversa F,Martelli MF,Velardi A.Natural killer cell recognition of missing self and haploidentical hematopoietic transplantation.Semin Cancer Biol,2006,16(5):404-411.
16 Vivier E,Nunes JA,Vely F.Natural killer cell signaling pathways.Science,2004,306(5701):1517-1519.
17 Farag SS,Caligiuri MA.Human natural killer cell development and biology.Blood Rev,2006,20(3):123-137.
18 Parham P.MHC class I molecules and KIRs in human history,health and survival.Nat Rev Immunol.2005,5(3):201-214.
19 Karre K.Natural killer cell recognition of missing self.Nat Immunol,2008,9(5):477-480.
20 Jones PA,Takai D.The role of DNA methylation in mammalian epigenetics.Science,2001,293(5532):1068-1070.
21 Trowsdale J,Barten R,Haude A,Stewart CA,Beck S,Wilson MJ.The genomic context of natural killer receptor extended gene families,Immunol Rev,2001,181:20-38.
22 Marsh SG,Parham P,Dupont B,Geraghty DE,Trowsdale J,Middleton D,Vilches C,Carrington M,Witt C,Guethlein LA,Shilling H,Garcia CA,Hsu KC,Wain H.Killer-cell immunoglobulin-like receptor(KIR) nomenclature report,2002.Eur J Immunogenet,2003,30(3):229-234.
23 Dimova DK,Dyson NJ.The E2F transcriptional network:old acquaintances with new faces.Oncogene,2005,24(17):2810-2826.
24 Stewart CA,van Bergen J,Trowsdale J.Different and divergent regulation of the KIR2DL4 and KIR3DL1 promoters.J Immunol,2003,170(12):6073-6081.
25 王长青,肖强,李雷,谢玉波,谭宁,宫志伟.E2F-1基因真核表达载体的构建及其对胃癌细胞株 MKN-45增殖的影响.癌症,2007,26(10):1064-1068.
26 Frommer M,McDonald LE,Millar DS,Collis CM,Watt F,Grigg GW,Molloy PL,Paul CL.A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands.Proc Nati Acad Sci USA,1992,89(5):1827-1831.
27 Thompson A,van der Slik AR,Koning F,van Bergen J.An improved RT-PCR method for the detection of killer-cell immunoglobulin-like receptor (kir) transcripts.Immunogenetics,2006,58(11):865-872.
28 van Bergen J,Stewart CA,van den Elsen PJ,Trowsdale J.Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptors.Eur J Immunol,2005,35(7):2191-2199.
29 Teixeira LA,Fricke CH,Bonorino CB,Bogo MR,Nardi NB.An efficient gene transfer system for hematopoietic cell line using transient and stable vectors.J Biotechnol,2001,88(2):159-165.
30 Lavrrar JL,Farnham PJ.The use of transient chromatin immunoprecipitation assays to test models for E2F1-specific transcriptional activation.J Biol Chem,2004,279(44):46343-46349.
31 Santourlidis S,Trompeter HI,Weinhold S,Eisermann B,Meyer KL,Wernet P,Uhrberg M.Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells.J Immunol,2002,169(8):4253-4261.
32 Gardiner-Garden M,Frommer M.CpG islands in vertebrate genomes.Mol Biol,1987,196(2):261-282.
33 Rius M,Stresemann C,Keller D,Brom M,Schirrmacher E,Keppler D,Lyko F.Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation.Mol Cancer Ther,2009,8(1):225-231.
34 Campanero MR,Armstrong MI,Flemington EK.CpG methylation as a mechanism for the regulation of E2F activity.Proc Nat Acad Sci USA,2000,97(12):6481-6486.
35 Cerwenka A,Lanier LL.Natural killer cells,viruses and cancer.Nat Rev Immunol,2001,1(1):41-49.
36 Vivier E,Tomasello E,Baratin M,Walzer T,Ugolini S.Functions of natural killer cells.Nat Immunol,2008,9(5):503-510.
37 Kelley J,Walter L,Trowsdale J.Comparative genomics of natural killer cell receptor gene clusters.PloS Genet,2005,1(2):129-139.
38 Santourlidis S,Graffmann N,Christ J,Uhrberg M.Lineage-specific transition of histone signatures in the killer cell Ig-like receptor locus from hematopoietic progenitor to NK cells.J Immunol,2008,180(1):418-425.
39 Chan HW,Kurago ZB,Stewart CA,Wilson MJ,Martin MP,Mace BE,Carrington M,Trowsdale J,Lutz CT.DNA methylation maintains allele-specific KIR gene expression in human natural killer cells.J Exp Med,2003,197(2):245-255.
40 Chan HW,Miller JS,Moore MB,Lutz CT.Epigenetic control of highly homologous killer Ig-like receptor gene alleles.J Immunol,2005,175(9):5966-5974.
41 Trundley A,Frebel H,Jones D,Chang C,Trowsdale J.Allelic expression patterns of KIR3DS1 and 3DL1 using the Z27 and DX9 antibodies.Eur J Immunol,2007,37(3):780-787.
42 Smyth MJ,Cretney E,Kelly JM,Westwood JA,Street SE,Yagita H,Takeda K,van Dommelen SL,Degli-Esposti MA,Hayakawa Y.Activation of NK cell cytotoxicity.Mol Immunol,2005,42(4):501-510.
43 Salcedo TW,Azzoni L,Wolf SF,Perussia B.Modulation of perforin and granzyme messenger RNA expression in human natural killer cells.J Immunol,1993,151(5):2511-2520.
44 DeBlaker-Hohe DF,Yamauchi A,Yu CR,Horvath-Arcidiacono JA,Bloom ET.IL-12 synergizes with IL-2 to induce lymphokine-activated cytotoxicity and perforin and granzyme gene expression in fresh human NK cells.Cell Immunol,1995,165(1):33-43.
45 Attwood JT,Yung RL,Richardson BC.DNA methylation and the regulation of gene transcription.Cell Mol Life Sci,2002,59(2):241-257.
46 Bruniquel D,Schwartz RH.Selective,stable demethylation of the interleukin-2 gene enhances transcription by an active process.Nat Immunol,2003,4(3):235-240.
47 Floess S,Freyer J,Siewert C,Baron U,Olek S,Polansky J,Schlawe K,Chang HD,Bopp T,Schmitt E,Klein-Hessling S,Serfling E,Hamann A,Huehn J.Epigenetic control of the foxp3 locus in regulatory T cells.PLoS Biol,2007,5(2):e38.
48 Hershkovitz O,Zilka A,Bar-Ilan A,Abutbul S,Davidson A,Mazzon M,K(u|¨)mmerer BM,Monsoengo A,Jacobs M,Porgador A.Dengue virus replicon expressing the nonstructural proteins suffices to enhance membrane expression of HLA class I and inhibit lysis by human NK cells.J Virol,2008,82(15):7666-7676.
49 Johnson DR.Differential expression of human major histocompatibility class I loci:HLA-A,-B,and-C.Hum Immunol,2000,61(4):389-396.
50 Reiter Z,Reiter Y,Fishelson Z,Shinitzky M,Kessler A,Loyter A,Nussbaum O,Rubinstein M.Resistance to NK cell-mediated cytotoxicity(in K-562 cells)does not correlate with class I MHC antigen levels.Immunobiology,1991,183(12):23-39.
51 Cooper MD.Inhibition of immune cell function.Immunol Rev,2008,224:7-10.
52 Trapani JA,Smyth MJ.Functional significance of the perforin/granzyme cell death pathway.Nat Rev Immunol,2002,2(10):735-747.
53 Heusel JW,Wesselschmidt RL,Shresta S,Russell JH,Ley TJ.Cytotoxic lymphocytes require granzyme B for the rapid induction of DNA fragmentation and apoptosis in allogeneic target cells.Cell,1994,76(6): 977-987.
54 Shi L,Kam CM,Powers JC,Aebersold R,Greenberg AH.Purification of three cytotoxic lymphocyte granule serine proteases that induce apoptosis through distinct substrate and target cell interactions.J Exp Med,1992,176(6):1521-1529.
55 Kagi D,Ledermann B,Biirki K,Seiler P,Odermatt B,Olsen KJ,Podack ER,Zinkernagel RM,Hengartner H.Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice.Nature,1994,369(6475):31-37.
56 Anfossi N,Andre P,Guia S,Falk CS,Roetynck S,Stewart CA,Breso V,Frassati C,Reviron D,Middleton D,Romagne F,Ugolini S,Vivier E.Human NK cell education by inhibitory receptors for MHC class I.Immunity,2006,25(2):331-342.
57 Perricone R,Perricone C,De Carolis C,Shoenfeld Y.NK cells in autoimmunity:A two-edg'd weapon of the immune system.Autoimmun Rev,2008,7(5):384-390.
58 Boyton RJ,Altmann DM.Natural killer cells,killer immunoglobulin-like receptors and human leucocyte antigen class I in disease.Clin Exp Immunol,2007,149(1):1-8.
1 Parham P.MHC class Ⅰ molecules and KIRs in human history,health and survival.Nat Rev Immunol,2005,5(3):201-214.
2 Marsh SG,Parham P,Dupont B,Geraghty DE,Trowsdale J,Middleton D,Vilches C,Carrington M,Witt C,Guethlein LA,Shilling H,Garcia CA,Hsu KC,Wain H.Killer-cell immunoglobulin-like receptor(KIR) nomenclature report,2002.Eur J Immunogenet,2003,30(3):229-234.
3 Vilches C,Parham P.KIR:diverse,rapidly evolving receptors of innate and adaptive immunity.Annu Rev Immunol,2002,20:217-251.
4 Maxwell LD,Wallace A,Middleton D,Curran MD.A common KIR2DS4deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey.Tissue Antigens,2002,60(3):254-258.
5 Long EO.Tumor cell recognation by natural killer cells.Semin Cancer Biol,2002,12(1):57-61.
6 Hsu KC,Chida S,Geraghty DE,Dupont B.The killer cell immunoglobulin-like receptor(KIR) genomic region:gene-order,haplotypes and allelic polymorphism.Immunol Rev,2002,190:40-52.
7 Yawata M,Yawata N,Draghi M,Little AM,Partheniou F,Parham P.Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function.J Exp Med,2006,203(3):633-645.
8 Young NT.Immunobiology of Natural Killer Lymphocytes in Transplantation.Transplantation,2004,78(1):1-6.
9 Watzl C,Long EO.Natural killer cell inhibitory receptors block actin cytoskeleton-dependent recruitment of 2B4(CD244)to lipid rafts.J Exp Med,2003,197(1):77-85.
10 Miller JS,McCullar V.Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2.Blood,2001,98(3):705-713.
11 Belkin D,Torkar M,Chang C,Barten R,Tolaini M,Haude A,Allen R,Wilson MJ,Kioussis D,Trowsdale J.Killer cell Ig-like receptor and leukocyte Ig-like receptor transgenic mice exhibit tissue-and cell-specific transgene expression.J Immunol,2003,171(6):3056-3063.
12 Doucey MA,Scarpellino L,Zimmer J,Guillaume P,Luescher IF,Bron C,Held W.Cis association of Ly49A with MHC class I restricts natural killer cell inhibition.Nat Immunol,2004,5(3):328-336.
13 Shilling HG,Young N,Guethlein LA,Cheng NW,Gardiner CM,Tyan D,Parham P.Genetic control of human NK cell repertoire.J Immunol,2002(1),169:239-247.
14 van Bergen J,Stewart CA,van den Elsen PJ,Trowsdale J.Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptors.Eur J Immunol,2005,35(7):2191-2199.
15 Trompeter HI,Gomez-Lozano N,Santourlidis S,Eisermann B,Wernet P,Vilches C,Uhrberg M.Three Structurally and Functionally Divergent Kinds of Promoters Regulate Expression of Clonally Distributed Killer Cell Ig-Like Receptors(KIR),of KIR2DL4,and of KIR3DL3.J Immunol,2005,174(7):4135-4143.
16 Chan HW,Kurago ZB,Stewart CA,Wilson MJ,Martin MP,Mace BE,Carrington M,Trowsdale J,Lutz CT.DNA methylation maintains allele-specific KIR gene expression in human natural killer cells.J Exp Med,2003,197(2):245-255.
17 Santourlidis S,Trompeter HI,Weinhold S,Eisermann B,Meyer KL,Wernet P, Uhrberg M.Crucial role of DNA methylation in determination of clonally distributed killer cell Ig-like receptor expression patterns in NK cells.J Immunol,2002,169(8):4253-4261.
18 Rouhi A,Gagnier L,Takei F,Mager DL.Evidence for epigenetic maintenance of Ly49a monoallelic gene expression.J Immunol,2006,176(5):2991-2999.
19 Turner BM.Cellular memory and the histone code.Cell,2002,111(3):285-291.
20 Chan HW,Miller JS,Moore MB,Lutz CT.Epigenetic control of highly homologous killer Ig-like receptor gene alleles.J Immunol,2005,175(9):5966-5974.