NKT细胞活化与C57BL/6J早孕小鼠流产机制的初步研究
摘要
背景NKT细胞是进化保守的T细胞亚群,兼具有固有性和适应性免疫细胞特性,可以与自体脂类抗原或α-半乳糖酰基鞘氨醇(α-Galcer)反应而活化。被脂类或糖脂抗原激活后能迅速产生大量细胞因子,并上调表达细胞毒分子。腹腔注射α-Galcer可活化NKT细胞并诱导早孕小鼠流产,Ito等(2000年)在PNAS上发表文章发现NKT敲除的小鼠不能被α-Galcer诱导而流产;Kinjo等检测了自然界中大量存在的鞘氨醇单胞菌属革兰阴性细菌的组成,发现大部分小鼠NKT细胞能识别α-Galcer的结构类似物——鞘氨醇,通过与CD1d的结合。这一研究成果发表在2005年的nature上。近年来发现妊娠激素特别是孕激素能调节抗体产生,降低单核细胞氧爆发;减少细菌产物引起的促炎症细胞因子的分泌,具有免疫调节的作用。
目的本研究拟建立体外诱导扩增小鼠NKT细胞的方法,探讨特异抗原和细胞因子对扩增的影响及评价扩增的NKT细胞的特性;评价在α-Galcer诱发性小鼠流产模型中,系统免疫功能的改变及α-Galcer导致早孕小鼠流产的机理。研究孕激素类药物醋酸甲羟孕酮(MPA)阻止α-Galcer诱导的流产作用。
方法(1)分离培养小鼠脾脏单个核细胞,在α-Galcer作用下,MTT法观察细胞药物敏感性;(2)PI法观察药物对细胞的影响;(3)检测α-Galcer和IL-2对扩增NKT细胞的影响;(4)流式细胞术(FACS)分选活化NKT细胞(NK1.1~+CD3~+CD69~+)和未活化NKT细胞(NK1.1~+CD3~+CD69~-),透射电子显微镜观察NKT细胞形态;(5)MTT检测细胞的杀伤活性。(6)腹腔注射α-Galcer(2μg/20g),诱导怀孕小鼠子宫蜕膜NKT活化,观察胚胎吸收率;(7)免疫组化法观察α-Galcer注射后观察胎盘孕激素受体和bcl-2表达;(8)孕鼠皮下注射MPA(0.5mg/只)2h后,腹腔注射α-Galcer,观察胚胎吸收率变化,检测MPA生物效应。
结果(1)50～100 ng/mL的α-Galcer作用24h,α-Galcer促小鼠脾细胞增殖活性与对照组相比显著增强(P＜0.05),最佳药物浓度为100ng/mL。(2)随药物浓度升高,亚二倍体细胞比例有升高趋势,当α-Galcer浓度超过200ng/mL时,此比例显著增加(P＜0.05)。(3)3例脾MNC分四组培养12天,α-Galcer组细胞和PBS对照组细胞很快凋亡,α-Galcer+IL-2组明显优于单用IL-2组(P＜0.05)。在α-Galcer和IL-2作用下,脾细胞总数在第4、8、12天分别增长1.6,2.8和3.4倍。(4)电子显微镜观察显示,活化的NKT细胞呈典型细胞活化改变,凋亡的NKT细胞,核固缩,致密形成新月小体,核膜破裂,凋亡小体形成。(5)8小时MTT杀伤实验中,可见NKT细胞对HL-60肿瘤细胞系具有剂量依赖性杀伤活性;对NK细胞敏感细胞系K562杀伤作用不明显。(6)腹腔注射α-Galcer,孕鼠胚胎吸收率与对照组相比明显升高;(7)注射α-Galcer后孕鼠子宫蜕膜处孕激素受体表达率明显上调,bcl-2表达率明显下降;(8)皮下注射MPA可降低α-Galcer所致的孕鼠流产。
结论本研究显示α-Galcer能刺激小鼠脾单个核细胞中的NKT细胞短期内大量扩增,IL-2是α-GalCer刺激扩增NKT细胞的基础细胞因子;体外活化的NKT细胞具有分泌细胞因子和细胞毒活性;
NKT细胞的直接作用及其分泌的细胞因子的潜能可能是α-Galcer所致孕鼠流产的主要原因。除了NKT细胞的重要作用,α-Galcer的药理作用似乎不能被排除;
MPA对免疫反应的调节能力可能是孕激素类阻止流产发生的一个关键因素。
Backgroud Natural killer T cells(NKT) are an evolutionary conserved sub-lineage of T cells that bridge the innate and adaptive systems and characterized by reactivity to self-glycolipids andα-galactosylceramide(α-Galcer) that are presented by monomorphic MHC class-Ⅰ-like molecule CDld.Upon antigen recognition,NKT cells can rapidly produce multiple cytokines and up-regulate cytotoxic molecules,α-Galcer can activate NKT cells and induce abortion in early pregnant mice when injected i.p..Ito and others found that NKT-knock-out mice can not be mediated abortion byα-Galcer.And this discovery was published in PNAS(2000).Kinjo and others examined compounds from Sphingomonas bacteria,Gram-negative bacteria which are highly abundant in the environment and found most mouse NKT cells recognize glycosphingolipids from Sphingomonas,whose structure isα-Galcer analogues, through CD1d binding.And this discovery was published in nature(2005).The recent discovery of pregnancy hormone,progesterone in particular,can regulate antibody production,decrease oxygen burst in monocytes and reduce proinflammation cytokines caused by bacterial products.That may be the role of immune regulation.
Objective we studied to optimize a method for expanding mouse NKT cells in vitro and searched the effect of specific antigen or varies of cytokines on the expansion.Then we determined the properties of expanded NKT cells.Meanwhile, we evaluated changes of immune function and mechanisms ofα-Galcer induced early abortion in a mouse model.Furthermore,the role of MPA in preventing abortion started byα-Galcer was preliminary explored in this study.
Methods Mouse splenic singal nuclear cells were isolated and cultured.Drug sensitivity toα-Galcer was analyzed with MTT and PI stain.Then the effect ofα-Galcer and rhIL-2 on cell expansion capability was performed.The activated or not NKT cells were selected by flow cytometrx(FACS),then the changes of ultrastructure of NKT cells were observed with transmission electron microscopy.Cytotoxic activation of NKT cells was detected by MTT assay. Pregnant C57BL/6J mice were injected i.p.withα-Galcer to activate NKT cells and rate of resorption was examined.The expressions of bcl-2 and PR in the decidua was examined by immunohistochemical staining with specific monoclonal antibodies.when MPA was injected i.h.2h beforeα-Galcer administration,the rate of resorption was examined and effect of MPA was explored.
Results At 24h after treated with 50～100 ng/mLα-Galcer,the proliferation activity of test NKT cells were significant higher than that of control(P＜0.05). And the best concentration was 100ng/mL.The rate of hypodiploid splenocytes increased when drug consentration rose.Once the consentration exceeded 200 ng/mL,the rate of that was significantly higher than control.Each of 3 cases of MNCs was divided into 4 groups.During 12d culture,cells from Groupα-Galcer and control were rapidly incurred apoptosis,a-Galcer+cytokine did better than cytokine only(P＜0.05).At the 4th,8th,12th day,the total number of spleen NKT cells was 1.6,2.8 and 3.4 times higher than control.Activated NKT cells displayed typical morphological characteristics of activated cells,and apoptosis NKT cells showed morphological changes including chromatin condensation,apoptotic body, and broken nuclear membrane.In 8-hrs MTT cytotoxicity assays,the anti-tumor effect of activated NKT cells was found in cell line HL60 but not in NK cell-sensitive cell,K562.Afterα-Galcer administration,the rate of abortion was significantly higher and the expression of bcl-2 in decidua was extremely lower than that of control.MPA could reduce this effect.
Conclusions In this study we had established culture conditions containingα-Galcer that allow for the short-term proliferation of large numbers of NKT cells from mouse spleenic MNCs.IL-2 was the essential cytokines for the expansion of NKT cells.Uponα-Galcer stimulation,NKT cells performed effect of secreting cytokines and cytotoxicity.
The effect ofα-Gal cer induced abortion in C57BL/J mice might associate with direct function of NKT cells and their potency of secreting cytokines.In addition to the important role of NKT cells,the pharmacological effects ofα-Galcer seemed not to be ruled out.
The ability of MPA to modulate the immune response might be a critical mechanism by which progestins prevent pregnancy loss.
目的本研究拟建立体外诱导扩增小鼠NKT细胞的方法,探讨特异抗原和细胞因子对扩增的影响及评价扩增的NKT细胞的特性;评价在α-Galcer诱发性小鼠流产模型中,系统免疫功能的改变及α-Galcer导致早孕小鼠流产的机理。研究孕激素类药物醋酸甲羟孕酮(MPA)阻止α-Galcer诱导的流产作用。
方法(1)分离培养小鼠脾脏单个核细胞,在α-Galcer作用下,MTT法观察细胞药物敏感性;(2)PI法观察药物对细胞的影响;(3)检测α-Galcer和IL-2对扩增NKT细胞的影响;(4)流式细胞术(FACS)分选活化NKT细胞(NK1.1~+CD3~+CD69~+)和未活化NKT细胞(NK1.1~+CD3~+CD69~-),透射电子显微镜观察NKT细胞形态;(5)MTT检测细胞的杀伤活性。(6)腹腔注射α-Galcer(2μg/20g),诱导怀孕小鼠子宫蜕膜NKT活化,观察胚胎吸收率;(7)免疫组化法观察α-Galcer注射后观察胎盘孕激素受体和bcl-2表达;(8)孕鼠皮下注射MPA(0.5mg/只)2h后,腹腔注射α-Galcer,观察胚胎吸收率变化,检测MPA生物效应。
结果(1)50～100 ng/mL的α-Galcer作用24h,α-Galcer促小鼠脾细胞增殖活性与对照组相比显著增强(P＜0.05),最佳药物浓度为100ng/mL。(2)随药物浓度升高,亚二倍体细胞比例有升高趋势,当α-Galcer浓度超过200ng/mL时,此比例显著增加(P＜0.05)。(3)3例脾MNC分四组培养12天,α-Galcer组细胞和PBS对照组细胞很快凋亡,α-Galcer+IL-2组明显优于单用IL-2组(P＜0.05)。在α-Galcer和IL-2作用下,脾细胞总数在第4、8、12天分别增长1.6,2.8和3.4倍。(4)电子显微镜观察显示,活化的NKT细胞呈典型细胞活化改变,凋亡的NKT细胞,核固缩,致密形成新月小体,核膜破裂,凋亡小体形成。(5)8小时MTT杀伤实验中,可见NKT细胞对HL-60肿瘤细胞系具有剂量依赖性杀伤活性;对NK细胞敏感细胞系K562杀伤作用不明显。(6)腹腔注射α-Galcer,孕鼠胚胎吸收率与对照组相比明显升高;(7)注射α-Galcer后孕鼠子宫蜕膜处孕激素受体表达率明显上调,bcl-2表达率明显下降;(8)皮下注射MPA可降低α-Galcer所致的孕鼠流产。
结论本研究显示α-Galcer能刺激小鼠脾单个核细胞中的NKT细胞短期内大量扩增,IL-2是α-GalCer刺激扩增NKT细胞的基础细胞因子;体外活化的NKT细胞具有分泌细胞因子和细胞毒活性;
NKT细胞的直接作用及其分泌的细胞因子的潜能可能是α-Galcer所致孕鼠流产的主要原因。除了NKT细胞的重要作用,α-Galcer的药理作用似乎不能被排除;
MPA对免疫反应的调节能力可能是孕激素类阻止流产发生的一个关键因素。
Backgroud Natural killer T cells(NKT) are an evolutionary conserved sub-lineage of T cells that bridge the innate and adaptive systems and characterized by reactivity to self-glycolipids andα-galactosylceramide(α-Galcer) that are presented by monomorphic MHC class-Ⅰ-like molecule CDld.Upon antigen recognition,NKT cells can rapidly produce multiple cytokines and up-regulate cytotoxic molecules,α-Galcer can activate NKT cells and induce abortion in early pregnant mice when injected i.p..Ito and others found that NKT-knock-out mice can not be mediated abortion byα-Galcer.And this discovery was published in PNAS(2000).Kinjo and others examined compounds from Sphingomonas bacteria,Gram-negative bacteria which are highly abundant in the environment and found most mouse NKT cells recognize glycosphingolipids from Sphingomonas,whose structure isα-Galcer analogues, through CD1d binding.And this discovery was published in nature(2005).The recent discovery of pregnancy hormone,progesterone in particular,can regulate antibody production,decrease oxygen burst in monocytes and reduce proinflammation cytokines caused by bacterial products.That may be the role of immune regulation.
Objective we studied to optimize a method for expanding mouse NKT cells in vitro and searched the effect of specific antigen or varies of cytokines on the expansion.Then we determined the properties of expanded NKT cells.Meanwhile, we evaluated changes of immune function and mechanisms ofα-Galcer induced early abortion in a mouse model.Furthermore,the role of MPA in preventing abortion started byα-Galcer was preliminary explored in this study.
Methods Mouse splenic singal nuclear cells were isolated and cultured.Drug sensitivity toα-Galcer was analyzed with MTT and PI stain.Then the effect ofα-Galcer and rhIL-2 on cell expansion capability was performed.The activated or not NKT cells were selected by flow cytometrx(FACS),then the changes of ultrastructure of NKT cells were observed with transmission electron microscopy.Cytotoxic activation of NKT cells was detected by MTT assay. Pregnant C57BL/6J mice were injected i.p.withα-Galcer to activate NKT cells and rate of resorption was examined.The expressions of bcl-2 and PR in the decidua was examined by immunohistochemical staining with specific monoclonal antibodies.when MPA was injected i.h.2h beforeα-Galcer administration,the rate of resorption was examined and effect of MPA was explored.
Results At 24h after treated with 50～100 ng/mLα-Galcer,the proliferation activity of test NKT cells were significant higher than that of control(P＜0.05). And the best concentration was 100ng/mL.The rate of hypodiploid splenocytes increased when drug consentration rose.Once the consentration exceeded 200 ng/mL,the rate of that was significantly higher than control.Each of 3 cases of MNCs was divided into 4 groups.During 12d culture,cells from Groupα-Galcer and control were rapidly incurred apoptosis,a-Galcer+cytokine did better than cytokine only(P＜0.05).At the 4th,8th,12th day,the total number of spleen NKT cells was 1.6,2.8 and 3.4 times higher than control.Activated NKT cells displayed typical morphological characteristics of activated cells,and apoptosis NKT cells showed morphological changes including chromatin condensation,apoptotic body, and broken nuclear membrane.In 8-hrs MTT cytotoxicity assays,the anti-tumor effect of activated NKT cells was found in cell line HL60 but not in NK cell-sensitive cell,K562.Afterα-Galcer administration,the rate of abortion was significantly higher and the expression of bcl-2 in decidua was extremely lower than that of control.MPA could reduce this effect.
Conclusions In this study we had established culture conditions containingα-Galcer that allow for the short-term proliferation of large numbers of NKT cells from mouse spleenic MNCs.IL-2 was the essential cytokines for the expansion of NKT cells.Uponα-Galcer stimulation,NKT cells performed effect of secreting cytokines and cytotoxicity.
The effect ofα-Gal cer induced abortion in C57BL/J mice might associate with direct function of NKT cells and their potency of secreting cytokines.In addition to the important role of NKT cells,the pharmacological effects ofα-Galcer seemed not to be ruled out.
The ability of MPA to modulate the immune response might be a critical mechanism by which progestins prevent pregnancy loss.
引文
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