化学修饰的iGb3类似物优势诱导NK细胞分泌Th1类细胞因子的分子机制研究
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摘要
目的自然杀伤T(natural killer T cells,NKT)细胞是一类能够识别非经典的MHCⅠ类分子CD1d所递呈的糖脂抗原的特殊类型的T淋巴细胞,同时表达NK和T细胞表面标志NK1.1和TCR。NKT细胞经内源性配体鞘糖脂iGb3(isoglobotrihexosylceramide )和外源性糖脂配体α-半乳糖神经酰胺(α-GalCer)活化后能够分泌IFN-γ、IL-4和IL-13等多种细胞因子,在抗肿瘤、抗病毒感染、自身免疫耐受和自身免疫性疾病中发挥着重要作用。但由于激活后的NKT细胞能够同时分泌Th1和Th2两型细胞因子,影响了iGb3或α-GalCer对免疫相关疾病的治疗效果,因而限制了其临床应用。因此,若能发现有效的途径,积极调控两型细胞因子的相对产生量,糖脂分子将会在临床应用中发挥更广泛的作用。
研究发现对α-GalCer的鞘鞍醇链进行截短所得的类似物OCH,可通过降低糖脂分子-CD1d复合物的稳定性和增强糖脂分子-TCR的亲和力来实现IL-4的优势分泌。而另有研究表明将连接糖基部分与另外两条链的O原子用C原子代替后产生的α-GalCer类似物α-C-GalCer,可以通过增强糖脂分子各部分之间连接的稳定性而延长了与CD1d和NKT细胞作用的时间来实现IFN-γ的优势分泌。提示,针对性改造糖脂,可以诱导NKT细胞Th1/ Th2型细胞因子的分泌。虽然有众多学者设计不同的位点对糖脂行各种修饰改造,并分析改造后的糖脂活化NKT细胞方面功能和结构的差异,但目前缺乏对于内源性配体iGb3进行改造的研究。
鉴于此,我们对iGb3和α-GalCe进行修饰,获得了一批化学修饰的iGb3和α-GalCe类似物,在前期工作中,我们初步筛选出两种类似物4-HO-iGb3和4'''-dh-iGb3具有优势诱导小鼠肝脏NKT细胞Th1型细胞因子的分泌能力。本研究采用四聚体染色法进一步筛选并确定经过化学修饰的iGb3类似物细胞因子的优势分泌,并在此基础上,深入探讨糖脂/APC/TCR间的相互作用以及细胞微环境等一些影响NKT细胞因子分泌的重要因素,为糖脂类分子的设计和临床应用提供新的策略和依据。
方法(1)流式细胞术法检测iGb3类似物和α-GalCer类似物对小鼠肝脏、脾脏中NKT细胞的数量和胞内细胞因子IFN-γ和IL-4的表达情况,以及转录因子STAT1和STAT6的STAT1磷酸化水平。(2)体外诱导小鼠骨髓来源树突装细胞的分化和成熟。(3) ELISA法检测化学修饰的iGb3类似物作用后小鼠血清中和细胞培养上清中细胞因子IFN-γ和IL-4的分泌水平。(4)实时定量PCR检测小鼠脾脏淋巴细胞中IFN-γ、IL-4、GATA-3和T-bet的基因表达情况。(5) QSAR软件分析糖脂分子与NKT细胞上TCR受体以及APC细胞上CD1d分子的亲和力高低。(6)蛋白质免疫印迹检测iGb3类似物对小鼠脾脏淋巴细胞转录因子T-bet和GATA-3的蛋白表达情况。
结果
一、化学修饰的iGb3类似物4’’’-dh-iGb3优势诱导小鼠肝脏和脾脏NKT细胞分泌IFN-γ
予C57BL/6小鼠腹腔注射iGb3及其类似物,发现与iGb3刺激组相比,化学修饰的iGb3类似物4’’’-dh-iGb3虽然并不增加肝脾NKT细胞的比例和数量,但可明显增强肝脾NKT细胞胞内IFN-γ的表达、分泌及血清中IFN-γ水平,而对Th2类细胞因子IL-4的表达和分泌无明显影响。用骨髓来源的DC负载糖脂,体外刺激小鼠的NKT细胞系,检测NKT细胞胞内细胞因子表达和上清细胞因子含量,亦得到了类似的结果。
二、4′′′-dh-iGb3可增强糖脂与CD1d、糖脂与NKT细胞TCR之间的结合力和稳定性
运用QSAR软件,在计算机上模拟糖脂、抗原递呈细胞的CD1d分子以及NKT细胞的TCR分子的空间结构,并进行分子结构之间的对接,发现在iGb3鞘鞍醇链引入HO可以形成一个疏水键,与原来酰基链上现有的HO一同直接地深入到CD1d分子形成的疏水性抗原结合口袋中,而增强了与CD1d分子上氨基酸Asp80(C)之间的亲和力;对糖基进行脱氧处理,使糖脂在与TCR分子氨基酸Lys167结合的空间位置由糖脂的此侧转变为糖脂的彼侧,使糖脂与TCR之间的结合分数由原来的3.3显著提高到4.9,增加了4'''-dh-iGb3与NKT细胞TCR的结合能力。即:修饰后的4’’’-dh-iGb3具有较iGb3更强的与抗原递呈细胞CD1d分子结合的亲和力及与NKT细胞TCR结合的稳定性。
三、4’’’-dh-iGb3能够上调Th1类细胞因子相关转录因子STAT1的磷酸化和T-bet的表达水平
予C57BL/6小鼠腹腔注射iGb3及其类似物或体外刺激小鼠的NKT细胞系,观察NKT细胞调控Th1/Th2类细胞因子表达相关转录因子的表达情况,发现与iGb3相比,4’’’-dh-iGb3能够上调NKT细胞调控Th1类细胞因子产生的转录因子STAT1的磷酸化和T-bet的表达,而调节Th2类细胞因子产生的转录因子STAT6的磷酸化和GATA-3的表达差异不显著。
结论(1) iGb3类似物4’’’-dh-iGb3能够诱导小鼠NKT细胞优势分泌Th1类细胞因子IFN-γ。(2) 4’’’-dh-iGb3可提高糖脂与CD1d、糖脂与NKT细胞TCR之间的稳定性和亲和力,从而促进NKT细胞的活化和Th1类细胞因子的分泌。(3) 4’’’-dh-iGb3可增强调控Th1/Th2分化的转录因子STAT1的磷酸化和T-bet的表达,从而促进NKT细胞IFN-γ的表达和分泌。(4) 4’’’-dh-iGb3可以作为新型免疫增强剂用于抗肿瘤和感染性疾病的治疗。
Objective Natural killer T (NKT) cells are a unique subset of the mature T lymphocytes that can recognize glycolipids presented by the nonclassical MHC class I molecule CD1d, as well as co-express the surface markers of NK cell and T cell. After activation viaα-galactosylceramide (α-GalCer), which is derived from a marine sponge and is well defined as an exogenous ligand of NKT cells, or an endogenous ligand, isoglobotrihexosylcera-mide (iGb3), NKT cells promptly secrete large amounts of both T helper 1 (Th1) cytokines ( such as IFN-γ), and T helper 2 (Th2) cytokines (such as interleukin (IL)-4 and interleukin (IL)-13), thereby exhibit multiple immunothe raputic effect in cancer, infectious diseases and autoimmune diseases (for example, multiple sclerosis, autoimmune diabetes and experimental autoimmune encephalomyelitis). However,the different cytokines produced by NKT cells after activation might have opposite effect,as Th1 cytokines often antagonize the action of Th2 cytokines and vice versa,which largely limits the clinic usage ofα-GalCer and iGb3.
In resent years, many researchers try to design, synthesize or make modification onα-GalCer to search for new NKT cell agonists that may have superior properties for the treatment of autoimmune and inflammatory diseases. The glycoceramide OCH, which is a derivative ofα-GalCer with a substantially shorter sphingosine chain, can stimulate NKT cells to preferentially produce Th2 cytokines, thereby indicating a potential application in the treatment of autoimmune conditions. Anotherα-GalCer analogue,α-C-GalCer, exerts more potent capacity to activate NKT cells and acts as a more effective trigger for IL-12 and IFN-γproduction, and thus is more valuable for resistance to tumor and infections. It was implication that modification of the ceramide chains could polarize the secretion of Th1 and Th2 cytokines by NKT cells. Although there are multitude investigations about the structure–activity relationship of modifiedα-GalCer, the exploration for chemically-modified iGb3 is absent.
In this regard, we synthesized some iGb3 analogues by chemcal synthetic methods and have found that two iGb3 analogues, 4-HO-iGb3 and 4?-dh-iGb3, can increases IFN-γproduction by hepatic NKT cells. In this study, tetramer staining technology was used to further identify their effect. To explore the molecular mechanism of their preferrential Th1-baised cytokine secretion capacity by NKT cells, the structure of the CD1d/glycolipid/TCR complex was analyzed by QSAR software, and expression and activation of some transcription factors involving in Th1/Th2 differenation were examined. This research will provide a new strategy and the theoretical basis for the designation and clinical application of glycolipids.
Methods
(1) Murine hepatic and splenic NKT cell number and intracellular cytokines IFN-γand IL-4 expression, as well as the phosphorlation level of transcription factors STAT1and STAT6 were analyzed by flow cytometry.
(2) Dendritic cells were induced from mouse bone marrow in vitro.
(3) The level of IFN-γand IL-4 in serum and the culture supernatants was determined by ELISA method.
(4) The gene expression of IFN-γ, IL-4, GATA-3 and T-bet was detected by real-time quantitative PCR.
(5) The affinity and stability between glycolipid and TCR, or glycolipid and CD1d were analyzed by QSAR softwar.
(6) The T-bet and GATA-3 expression in protein level was detected by Western blot.
Results
1. Chemical modified iGb3 analogue 4'''-dh-iGb3 preferentially increased IFN-γproduction by hepatic and splenic NKT cells.
Firstly, C57BL/6 mice were treated with iGb3 and its analogues intraperitoneally, we found that, compared with iGb3, chemical modified iGb3 analogues 4'''-dh-iGb3 did not increase hepatic and splenic NKT cells in proportion and quantity, but significantly enhanced IFN-γsecretion in serum, and up-regulated the levels of IFN-γ+NKT cells of liver and spleen, while the expression and secretion of Th2 type cytokine IL-4 were not influenced significantly. Similar results were obtained by murine NKT cell lines stimulated with bone marrow-derived DC loading glycolipids in vitro.
2. 4'''-dh-iGb3 increased the affinity between glycolipid and CD1d, and enhanced the stability of binding between glycolipidand TCR.
The spatial structure and docking between glycolipid, TCR and CD1d was established on computer by QSAR software. Our results revealed that the hydroxy group introduced in the phytosphingosine of iGb3, as well as the original hydroxy group in the acyl chain, inserted into antigen-binding hydrophobic pocket of CD1d molecules directly, and thus enhanced the affinity between glycolipid and amino acids Asp80 (C) of CD1d molecules. Removing the 4’’’hydroxyl group of the terminal galactose of iGb3, carried amino acid Lys167 of TCR from this side to the other side of glycolipid in the spatial location, thus increased the combination score between glycolipid and TCR from 3.3 to 4.9. Therefore, the binding affinity between 4’’’-dh-iGb3 and TCR of NKT cells was enhanced significantly. These results indicated that 4'''-dh-iGb3 has hiher binding affinity to CD1d of antigen-presenting cells, andstronger stability of binding to TCR of NKT cell than iGb3.
3. 4'''-dh-iGb3 up-regulated Th1-type cytokines-directed transcription factor STAT1 phosphorylation and T-bet expression.
C57BL/6 mice were injected with iGb3 and its analogues intraperitoneally, or mouse NKT cell lines were stimulated in vitro. The expression levels of transcription factors STAT1 and T-bet were examined. The results showed that, compared with iGb3, 4’’’-dh-iGb3 stimulation increased the level of STAT1 phosphorylation and T-bet expresssion, while the Th2 type cytokines associated transcription factor STAT6 phosphorylation and GATA-3 expression were not changed significantly.
Conclusions
(1) iGb3 analogue 4'''-dh-iGb3 stimulates Th1-baised immune responses of mouse NKT cells.
(2) 4'''-dh-iGb3 increases the stability and affinity between CD1d glycolipid/NKT TCR complex, so that promotes NKT cell activation and Th1-type cytokine secretion.
(3) 4'''-dh-iGb3 up-regulates Th1-type cytokines associated transcription factor STAT1 phosphorylation and T-bet expression.
(4) 4'''-dh-iGb3 could be used as a new immune stimulator for treatment of cancer and infectious diseases.
研究发现对α-GalCer的鞘鞍醇链进行截短所得的类似物OCH,可通过降低糖脂分子-CD1d复合物的稳定性和增强糖脂分子-TCR的亲和力来实现IL-4的优势分泌。而另有研究表明将连接糖基部分与另外两条链的O原子用C原子代替后产生的α-GalCer类似物α-C-GalCer,可以通过增强糖脂分子各部分之间连接的稳定性而延长了与CD1d和NKT细胞作用的时间来实现IFN-γ的优势分泌。提示,针对性改造糖脂,可以诱导NKT细胞Th1/ Th2型细胞因子的分泌。虽然有众多学者设计不同的位点对糖脂行各种修饰改造,并分析改造后的糖脂活化NKT细胞方面功能和结构的差异,但目前缺乏对于内源性配体iGb3进行改造的研究。
鉴于此,我们对iGb3和α-GalCe进行修饰,获得了一批化学修饰的iGb3和α-GalCe类似物,在前期工作中,我们初步筛选出两种类似物4-HO-iGb3和4'''-dh-iGb3具有优势诱导小鼠肝脏NKT细胞Th1型细胞因子的分泌能力。本研究采用四聚体染色法进一步筛选并确定经过化学修饰的iGb3类似物细胞因子的优势分泌,并在此基础上,深入探讨糖脂/APC/TCR间的相互作用以及细胞微环境等一些影响NKT细胞因子分泌的重要因素,为糖脂类分子的设计和临床应用提供新的策略和依据。
方法(1)流式细胞术法检测iGb3类似物和α-GalCer类似物对小鼠肝脏、脾脏中NKT细胞的数量和胞内细胞因子IFN-γ和IL-4的表达情况,以及转录因子STAT1和STAT6的STAT1磷酸化水平。(2)体外诱导小鼠骨髓来源树突装细胞的分化和成熟。(3) ELISA法检测化学修饰的iGb3类似物作用后小鼠血清中和细胞培养上清中细胞因子IFN-γ和IL-4的分泌水平。(4)实时定量PCR检测小鼠脾脏淋巴细胞中IFN-γ、IL-4、GATA-3和T-bet的基因表达情况。(5) QSAR软件分析糖脂分子与NKT细胞上TCR受体以及APC细胞上CD1d分子的亲和力高低。(6)蛋白质免疫印迹检测iGb3类似物对小鼠脾脏淋巴细胞转录因子T-bet和GATA-3的蛋白表达情况。
结果
一、化学修饰的iGb3类似物4’’’-dh-iGb3优势诱导小鼠肝脏和脾脏NKT细胞分泌IFN-γ
予C57BL/6小鼠腹腔注射iGb3及其类似物,发现与iGb3刺激组相比,化学修饰的iGb3类似物4’’’-dh-iGb3虽然并不增加肝脾NKT细胞的比例和数量,但可明显增强肝脾NKT细胞胞内IFN-γ的表达、分泌及血清中IFN-γ水平,而对Th2类细胞因子IL-4的表达和分泌无明显影响。用骨髓来源的DC负载糖脂,体外刺激小鼠的NKT细胞系,检测NKT细胞胞内细胞因子表达和上清细胞因子含量,亦得到了类似的结果。
二、4′′′-dh-iGb3可增强糖脂与CD1d、糖脂与NKT细胞TCR之间的结合力和稳定性
运用QSAR软件,在计算机上模拟糖脂、抗原递呈细胞的CD1d分子以及NKT细胞的TCR分子的空间结构,并进行分子结构之间的对接,发现在iGb3鞘鞍醇链引入HO可以形成一个疏水键,与原来酰基链上现有的HO一同直接地深入到CD1d分子形成的疏水性抗原结合口袋中,而增强了与CD1d分子上氨基酸Asp80(C)之间的亲和力;对糖基进行脱氧处理,使糖脂在与TCR分子氨基酸Lys167结合的空间位置由糖脂的此侧转变为糖脂的彼侧,使糖脂与TCR之间的结合分数由原来的3.3显著提高到4.9,增加了4'''-dh-iGb3与NKT细胞TCR的结合能力。即:修饰后的4’’’-dh-iGb3具有较iGb3更强的与抗原递呈细胞CD1d分子结合的亲和力及与NKT细胞TCR结合的稳定性。
三、4’’’-dh-iGb3能够上调Th1类细胞因子相关转录因子STAT1的磷酸化和T-bet的表达水平
予C57BL/6小鼠腹腔注射iGb3及其类似物或体外刺激小鼠的NKT细胞系,观察NKT细胞调控Th1/Th2类细胞因子表达相关转录因子的表达情况,发现与iGb3相比,4’’’-dh-iGb3能够上调NKT细胞调控Th1类细胞因子产生的转录因子STAT1的磷酸化和T-bet的表达,而调节Th2类细胞因子产生的转录因子STAT6的磷酸化和GATA-3的表达差异不显著。
结论(1) iGb3类似物4’’’-dh-iGb3能够诱导小鼠NKT细胞优势分泌Th1类细胞因子IFN-γ。(2) 4’’’-dh-iGb3可提高糖脂与CD1d、糖脂与NKT细胞TCR之间的稳定性和亲和力,从而促进NKT细胞的活化和Th1类细胞因子的分泌。(3) 4’’’-dh-iGb3可增强调控Th1/Th2分化的转录因子STAT1的磷酸化和T-bet的表达,从而促进NKT细胞IFN-γ的表达和分泌。(4) 4’’’-dh-iGb3可以作为新型免疫增强剂用于抗肿瘤和感染性疾病的治疗。
Objective Natural killer T (NKT) cells are a unique subset of the mature T lymphocytes that can recognize glycolipids presented by the nonclassical MHC class I molecule CD1d, as well as co-express the surface markers of NK cell and T cell. After activation viaα-galactosylceramide (α-GalCer), which is derived from a marine sponge and is well defined as an exogenous ligand of NKT cells, or an endogenous ligand, isoglobotrihexosylcera-mide (iGb3), NKT cells promptly secrete large amounts of both T helper 1 (Th1) cytokines ( such as IFN-γ), and T helper 2 (Th2) cytokines (such as interleukin (IL)-4 and interleukin (IL)-13), thereby exhibit multiple immunothe raputic effect in cancer, infectious diseases and autoimmune diseases (for example, multiple sclerosis, autoimmune diabetes and experimental autoimmune encephalomyelitis). However,the different cytokines produced by NKT cells after activation might have opposite effect,as Th1 cytokines often antagonize the action of Th2 cytokines and vice versa,which largely limits the clinic usage ofα-GalCer and iGb3.
In resent years, many researchers try to design, synthesize or make modification onα-GalCer to search for new NKT cell agonists that may have superior properties for the treatment of autoimmune and inflammatory diseases. The glycoceramide OCH, which is a derivative ofα-GalCer with a substantially shorter sphingosine chain, can stimulate NKT cells to preferentially produce Th2 cytokines, thereby indicating a potential application in the treatment of autoimmune conditions. Anotherα-GalCer analogue,α-C-GalCer, exerts more potent capacity to activate NKT cells and acts as a more effective trigger for IL-12 and IFN-γproduction, and thus is more valuable for resistance to tumor and infections. It was implication that modification of the ceramide chains could polarize the secretion of Th1 and Th2 cytokines by NKT cells. Although there are multitude investigations about the structure–activity relationship of modifiedα-GalCer, the exploration for chemically-modified iGb3 is absent.
In this regard, we synthesized some iGb3 analogues by chemcal synthetic methods and have found that two iGb3 analogues, 4-HO-iGb3 and 4?-dh-iGb3, can increases IFN-γproduction by hepatic NKT cells. In this study, tetramer staining technology was used to further identify their effect. To explore the molecular mechanism of their preferrential Th1-baised cytokine secretion capacity by NKT cells, the structure of the CD1d/glycolipid/TCR complex was analyzed by QSAR software, and expression and activation of some transcription factors involving in Th1/Th2 differenation were examined. This research will provide a new strategy and the theoretical basis for the designation and clinical application of glycolipids.
Methods
(1) Murine hepatic and splenic NKT cell number and intracellular cytokines IFN-γand IL-4 expression, as well as the phosphorlation level of transcription factors STAT1and STAT6 were analyzed by flow cytometry.
(2) Dendritic cells were induced from mouse bone marrow in vitro.
(3) The level of IFN-γand IL-4 in serum and the culture supernatants was determined by ELISA method.
(4) The gene expression of IFN-γ, IL-4, GATA-3 and T-bet was detected by real-time quantitative PCR.
(5) The affinity and stability between glycolipid and TCR, or glycolipid and CD1d were analyzed by QSAR softwar.
(6) The T-bet and GATA-3 expression in protein level was detected by Western blot.
Results
1. Chemical modified iGb3 analogue 4'''-dh-iGb3 preferentially increased IFN-γproduction by hepatic and splenic NKT cells.
Firstly, C57BL/6 mice were treated with iGb3 and its analogues intraperitoneally, we found that, compared with iGb3, chemical modified iGb3 analogues 4'''-dh-iGb3 did not increase hepatic and splenic NKT cells in proportion and quantity, but significantly enhanced IFN-γsecretion in serum, and up-regulated the levels of IFN-γ+NKT cells of liver and spleen, while the expression and secretion of Th2 type cytokine IL-4 were not influenced significantly. Similar results were obtained by murine NKT cell lines stimulated with bone marrow-derived DC loading glycolipids in vitro.
2. 4'''-dh-iGb3 increased the affinity between glycolipid and CD1d, and enhanced the stability of binding between glycolipidand TCR.
The spatial structure and docking between glycolipid, TCR and CD1d was established on computer by QSAR software. Our results revealed that the hydroxy group introduced in the phytosphingosine of iGb3, as well as the original hydroxy group in the acyl chain, inserted into antigen-binding hydrophobic pocket of CD1d molecules directly, and thus enhanced the affinity between glycolipid and amino acids Asp80 (C) of CD1d molecules. Removing the 4’’’hydroxyl group of the terminal galactose of iGb3, carried amino acid Lys167 of TCR from this side to the other side of glycolipid in the spatial location, thus increased the combination score between glycolipid and TCR from 3.3 to 4.9. Therefore, the binding affinity between 4’’’-dh-iGb3 and TCR of NKT cells was enhanced significantly. These results indicated that 4'''-dh-iGb3 has hiher binding affinity to CD1d of antigen-presenting cells, andstronger stability of binding to TCR of NKT cell than iGb3.
3. 4'''-dh-iGb3 up-regulated Th1-type cytokines-directed transcription factor STAT1 phosphorylation and T-bet expression.
C57BL/6 mice were injected with iGb3 and its analogues intraperitoneally, or mouse NKT cell lines were stimulated in vitro. The expression levels of transcription factors STAT1 and T-bet were examined. The results showed that, compared with iGb3, 4’’’-dh-iGb3 stimulation increased the level of STAT1 phosphorylation and T-bet expresssion, while the Th2 type cytokines associated transcription factor STAT6 phosphorylation and GATA-3 expression were not changed significantly.
Conclusions
(1) iGb3 analogue 4'''-dh-iGb3 stimulates Th1-baised immune responses of mouse NKT cells.
(2) 4'''-dh-iGb3 increases the stability and affinity between CD1d glycolipid/NKT TCR complex, so that promotes NKT cell activation and Th1-type cytokine secretion.
(3) 4'''-dh-iGb3 up-regulates Th1-type cytokines associated transcription factor STAT1 phosphorylation and T-bet expression.
(4) 4'''-dh-iGb3 could be used as a new immune stimulator for treatment of cancer and infectious diseases.
引文
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1. Matsuda JL, Mallevaey, Scott-Browne J, et al. CD1d-restricted iNKT cells, the‘Swiss-Army knife’of the immune system [J]. Curr Opin Immunol, 2008, 20(5):1~11.
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5. Benlagha K, Wei DG, Veiga J, et al. Characterization of the early stages of thymic NKT cell development [J]. J Exp Med, 2005, 202(4): 485~492.
6. Townsend MJ, Weinmann AS, Matsuda JL, et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells [J]. J Exp Med, 2006, 203(3): 755~766.
7. Kim PJ, Pai SY, Brigl M, et al. GATA-3 regulates the development and function of invariant NKT cells [J]. J Immunol, 2006, 177 (10): 6650~6659.
8. Chung Y, Nurieva R, Esashi E, et al. A critical role of costimulation during intrathymic development of invariant NKT cells [J]. J Immunol, 2008, 180(4): 2276~2283.
9. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development [J]. Proc Natl Acad Sci U S A, 2008, 105(13): 5207~5212.
10. Eger KA, Sundrud MS, Motsinger AA, et al. Human natural killer T cells are heterogeneous in their capacity to reprogram their effectors functions [J]. PLoS ONE, 2006, 1 (1):1~9.
11. Baev DV, Peng XH, Song L, et al. Distinct homeostatic requirements of CD4+ and CD4– subsets of Vα24-invariant natural killer T cells in humans [J]. Blood, 2004, 104 (13): 4150~4156.
12. Lee PT, Benlagha K, Teyton L, et al. Distinct functional lineages of human Vα24 natural killer T cells [J]. J Exp Med, 2002, 195(5): 637~641.
13. Fujii S, Shimizu K, Kronenberg, M, et al. Prolonged IFN-γproducing NKT response induced withα-galactosylceramide-loaded DCs [J]. Nat Immunol, 2002, 3(9): 867~874.
14. Oki S, Chiba A, Yamamura T, et al. The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells[J]. J Clin Invest, 2004, 113(11): 1631~1640.
15. McCarthy C, shepherd D, Fleire S, et al. The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation [J]. J Exp Med, 2007, 204(5):1131~1144.
16. Shang P, Zhang C, Xia C, et al. Chemical modification of iGb3 increases IFN-gamma production by hepatic NKT cells [J]. Int Immunopharmacol, 2008, 8(5):645~653.
17. Yang Y, Ueno A, Bao M, et al. Control of NKT Cell differentiation by tissue-specific microenvironments [J]. J Immunol, 2003, 171(11): 5913~5920.
18. OnoéK, Yanagawa Y, Minami K, et al. Th1 or Th2 balance regulated by interaction between dendritic cells and NKT cells [J]. Immunol Res, 2007, 38(1-3):319~32.
19. Wiethe C, Debus A, Mohrs M, et al. Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection [J]. J Immunol, 2008, 180(7): 4371~4381.
2. Bendelac A, Lantz O, Quimby ME,et al. CD1 recognition by mouse NK1+ T lymphocytes [J]. Science, 1995, 268(5212): 863-865.
3. Benlagha K, Wei DG, Veiga J, et al. Characterization of the early stages of thymic NKT cell development [J]. J Exp Med, 2005, 202(4): 485-492.
4. Godfrey DI, Berzins SP. Control points in NKT-cell development [J]. Nat Rev Immunol, 2007, 7(7): 505-518.
5. Matsuda JL, Mallevaey, Scott-Browne J, et al. CD1d-restricted iNKT cells, the‘Swiss-Army knife’of the immune system [J]. Curr Opin Immunol, 2008, 20(5):1-11.
6. Bendelac A, Rivera MN, Park SH, et al. Mouse CD1-specifc NK1 T cells: development, specifcity, and function [J]. Annu Rev Immunol, 1997, 15(1): 535-562.
7. Kim CH, Johnston B, Butcher EC. Trafficking machinery of NKT cells: shared and differential chemokine receptor expression among Valpha V(+) beta11(+) NKT cell subsets with distinct cytokine-producing capacity[ J ]. Blood, 2002, 100(1): 11-16.
8. Kronenberg M, Naidenko O, Koning F. Right on target: novel approaches for the direct visualization of CD1-specifc T cell responses [J]. Proc Natl Acad Sci U S A, 2001, 98(6): 2950-2952.
9. Kim PJ, Pai SY, Brigl M, et al. GATA-3 regulates the development and function of invariant NKT cells [J]. J Immunol, 2006, 177(10): 6650-6659.
10. Matsuda JL, Naidenko OV, Gapin L, et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers. J Exp Med, 2000, 192(5):741.
11. Huber S, Sartini D, Exley M. Role of CD1d in coxsackievirus B3-induced myocarditis [J]. J Immunol, 2003, 170(6): 3147-3153.
12. Sidobre S, Kronenberg M. CD1 tetramers: a powerful tool for the analysis of glycolipid-reactive T cells [J]. J Immunol Methods, 2002; 268(1): 107-121.
13. Calabi F, Milstein C. The molecular biology of CD1d [J]. Semin Immunol, 2000, 12(6): 503-509.
14. Ko SY, Ko HJ, Chang WS, et al. Alpha-Galactosylceramide can act as a nasal vaccine adjuvant inducing protective immune responses against viral infection and tumor [J]. J Immunol 2005, 175(5):3309-17.
15. Smyth MJ, Wallace ME, Nutt SL, et al. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer [J]. J Exp Med, 2005, 201(12):1973-85.
16. Singh AK, Wilson MT, Hong S, et al. Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis [J]. J Exp Med, 2001, 194(12):1801-11.
17. Ito K, Karasawa M, Kawano T, et al. Involvement of decidual Valpha14 NKT cells inabortion [J].Proc Natl Acad Sci U S A, 2000(2), 97:740-4.
18. Oki S, Chiba A, Yamamura T, et al. The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells[ J ]. J Clin Invest, 2004, 113(11): 1631-1640.
19. Fujii S, Shimizu K, Kronenberg, M, et al. Prolonged IFN-γproducing NKT response induced withα-galactosylceramide-loaded DCs [J]. Nat Immunol, 2002, 3(9): 867-874.
20. Schmieg J, Yang G, Franck RW, et al. Superior protection against malaria and melanoma metastases by a C-glycoside analogue of the natural killer T cell ligand alpha-Galactosylceramide[ J ]. J Exp Med, 2003, 198(11):1631–1641.
21. Zhou D, Mattner J, Cantu III C, et al. Lysosomal glycosphingolipid recognition by NKT cells [ J ]. Scienc,e 2004,306(5702):1786-1789.
22. Shang P, Zhang C, Xia C, et al. Chemical modification of iGb3 increases IFN-gamma production by hepatic NKT cells [J]. Int Immunopharmacol, 2008,8(5):645-653.
23. Ste′phane S, Kirsten J L, Lise B-S,et al. The T cell antigen receptor expressed by Vα14iNKT cells has a unique mode of glycosphingolipid antigen recognition [J] .Proc Natl Acad Sci U S A 2004, 101(33):12254–12259.
24. Bolen BJ,Brugge JS.Leukocyte protein tyrosine kinases:Potentail targets for drug discovery[J].Annu Rev Immunol,1997,15(1):371-404.
25. Ihle JN,Witthuhn BA,Quelle FW,et al.Signal through the hematopoietic cytokine receptors[J].Annu Rev Immunol,1995,13:369-398.
26. Kim PJ, Pai SY, Brigl M, et al. GATA-3 regulates the development and function of invariant NKT cells [J]. J Immunol, 2006, 177 (10): 6650-6659
27. Chung Y, Nurieva R, Esashi E, et al. A critical role of costimulation during intrathymic development of invariant NKT cells [J]. J Immunol, 2008, 180(4): 2276-2283.
28. Yu S, Cantorna MT. The vitamin D receptor is required for iNKT cell development [J]. Proc Natl Acad Sci U S A [J], 2008, 105(13): 5207-5212.
29. Matsuda JL, Naidenko OV, Gapin L,et al. Tracking the response of natural killer T cells to a glycolipid antigen using CD1d tetramers [J]. J Exp Med, 2000; 192(5): 741-754.
30. Lee PT, Benlagha K, Teyton L, et al. Distinct functional lineages of human Vα24 natural killer T cells [J]. J Exp Med, 2002, 195(5): 637-641.
31. Yang Y, Ueno A, Bao M, et al. Control of NKT Cell Differentiation by Tissue-Specific Microenvironments [J]. J Immunol, 2003,171(11) : 5913–5920.
32. OnoéK, Yanagawa Y, Minami K, et al. Th1 or Th2 balance regulated by interaction between dendritic cells and NKT cells [J]. Immunol Res, 2007, 38(1-3):319-32.
33. Wiethe C, Debus A, Mohrs M, et al. Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection [J]. J Immunol, 2008, 180(7): 4371-4381.
34. Godfrey DI, Macdonald HR, Kronenberg M, et al. NKT cells: what’s in a name?[J]. Nat Rev Immunol, 2004, 4(3): 231-237.
35. Watarai H, Nakagawa R, Omori Miyake M, et al. Methods for detection, isolation and culture of mouse and human invariant NKT cells[J]. Nat protocols, 2008, 1(3): 70-78.
36. Ikarashi Y, Akira Iizuka A, Heike Y, et al. Cytokine production and migration of in vitro expanded NK1.1-invariant Vα14 natural killer T (Vα14i NKT) cells usingα galactosylceramide and IL-2[J]. Immunol Lett, 2005, 101(2): 160-167.
37. Van Kaer L. Alpha-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles[J]. Nat Rev Immunol 2005, 5(1): 31-42.
38. Kamada N, Iijima H, Kimura K. Crucial amino acid residues of mouse CD1d for glycolipid ligand presentation to V(alpha)14 NKT cells Harada M, Shimizu E, Motohashi Si, Kawano T, Shinkai H, Nakayama T, Sakai T, Brossay L, Kronenberg M, Taniguchi M. Int Immunol, 2001, 13(7): 853-861.
39. Natalie A. Borg1, Kwok S. CD1d–lipid-antigen recognition by the semi-invariant NKT T-cell receptor[J]. Nature, 2007, 448(7149):44-49.
40. Townsend MJ, Weinmann AS, Matsuda JL, et al. T-bet regulates the terminal maturation and homeostasis of NK and Vα14i NKT cells [J]. J Exp Med, 2006, 203(3): 755-766.
41. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 commitment [J].Cell, 2000, 100(6):655-669.
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