IFN-γ对单核细胞分化、MICs表达的影响以及MICs在单核细胞-NK/T细胞“对话”中的作用
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摘要
NK细胞及CD8~+T细胞分别是天然及适应性细胞免疫的主要效应细胞。活化的NK细胞或CD8~+T细胞具有相似的效应功能:针对靶细胞的细胞毒作用和细胞因子的分泌,其中IFN-γ是活化NK细胞或CD8~+T细胞分泌的最常见和最重要的细胞因子。IFN-γ不仅具有直接的抗病毒作用,更能对体内多种细胞(包括淋巴细胞自身)发挥免疫调节和修饰的作用。
NKG2D是一种表达于NK细胞、巨噬细胞、CD8~+T细胞及γδTCR~+T细胞表面的活化受体,由NKG2D启动的信号可直接活化NK细胞和巨噬细胞;对于T细胞,NKG2D提供重要的共刺激信号。MHC-I类链相关分子(MICs)是最早被发现且研究较充分的NKG2D受体的配体。MICs定位于HLA-I类基因区,在MICA-MICG七个成员中,目前认为MICA及MICB是能够被转录翻译的功能基因。作为一种应激的标记分子,MICs广泛表达于处于热休克、氧化应激、感染及恶变的细胞表面,当它被NK/T细胞表面的NKG2D受体识别并结合后,即可启动NK细胞或T细胞介导的免疫应答,最终导致这些“异常”细胞被清除。MICs分子也低水平表达于正常肠上皮细胞、某些内皮细胞及成纤维细胞表面;在单核细胞、某些角质细胞及活化的T细胞胞浆内,也检测到MIC蛋白的表达。正常细胞表面低水平或阴性表达MICs分子,可能是机体的一种自我保护机制。
单核细胞是单核-巨噬系统的主要成份。体内单核细胞正常情况下处于免疫静息状态,但在适宜的条件作用下,它可以通过转化为DCs或者分泌大量细胞因子来参与或调节免疫应答。最近研究发现,单核细胞与NK细胞或T细胞之间存在着对话机制,并且淋巴细胞产生的IFN-γ及细胞间的直接接触可能是介导单核细胞与淋巴细胞相互作用的关键环节。但对于IFN-γ在调节单核细胞与淋巴细胞之间对话的具体分子机制,目前仍不清楚。考虑到NKG2D在调控淋巴细胞活化及其在天然免疫及适应性免疫应答之间的重要“桥梁”作用,我们猜测NKG2D受体/配体系统极可能也参与了IFN-γ介导的淋巴细胞/单核细胞之间的对话。
虽然HBV特异性T细胞应答是机体清除HBV的关键,但NK细胞在HBV感染早期控制病毒复制及辅助HBV特异性CTLs产生方面也扮演重要角色。HBV慢性感染常常伴有NK细胞数量和功能的下降,另一方面,慢性乙肝患者对外源性IFN-γ治疗呈低反应性。HBV慢性感染的NK细胞功能受损是否与单核细胞与NK细胞间交互互作用障碍有关?IFN-γ对慢性乙肝患者单核细胞是否有正常的免疫调节和修饰作用?也是有待回答的问题。
基于以上研究背景和存在问题,我们从以下方面进行了相关研究:1、从健康志愿者PBMCs中分选单核细胞,采用流式细胞术和形态观测的方法检测了细胞因子IFN-γ、TNF-α、IFN-α刺激前后单核细胞形态学变化和有关表型分子CD14、CD1a、CD80、CD83、CD86、HLA-DR的表达变化;2、流式细胞术检测细胞因子IFN-γ、TNF-α、IFN-α对正常PBMCs、分选的原代单核细胞以及单核细胞系U937、THP-1表面MIC表达的影响;3、采用RT-PCR及Western blot检测了IFN-γ刺激前后单核细胞MICs的表达;4、将IFN-γ刺激的单核细胞与异体NK细胞进行共培养,采用流式细胞术检测NK细胞活化标志分子CD69及胞内IFN-γ的表达,同时以~(51)Cr释放试验分析了NK细胞对其靶细胞K562细胞的细胞毒效应,观察单核细胞表面MICs分子及膜结合型IL-15(mIL-15)在NK细胞活化及NKG2D受体维持中的作用;5、采用磁珠活化NK细胞,收集活化NK细胞培养上清,与单核细胞进行培养后,再将单核细胞与自体CD8~+CD28~-T细胞进行共培养,流式细胞术检测单核细胞MICs及T细胞活化相关分子CD25、CD62L的表达;6、采用流式细胞术及~(51)Cr释放试验检测了IFN-γ刺激的慢性乙肝患者单核细胞与正常人NK细胞共培养后,NK细胞的活化分子CD69及胞内IFN-γ的表达,以及NK细胞对K562细胞的杀伤能力;7、流式细胞检测并比较了IFN-γ刺激后,15例健康志愿者及13例慢性乙肝患者单核细胞表面MICs及mIL-15的表达差异。
我们的结果发现:1、IFN-γ能促进单核细胞粘附聚集,单核细胞簇集形成独特的“细胞小岛”样结构,IFN-γ刺激的单核细胞呈梭形或多角形,表面有突起形成;IFN-α有较微弱的促进单核细胞簇集的作用,IFN-α刺激的单核细胞形成较多突起,形似星形;TNF-α对单核细胞形态无明显影响;2、IFN-γ刺激5 day后,单核细胞同时具有DCs及单核细胞表型特征,体现为由CD14~+CD1a~-CD83~-转变为CD14~+CD1a~+CD83~+,但CD14表达水平明显下降,IFN-γ还能促进单核细胞CD80、CD86及HLA-DR的表达;IFN-α也能促进单核细胞CD80、CD83、CD86及HLA-DR的表达,能下调CD14表达,但不能上调CD1a表达,上调CD83的能力较弱;TNF-α对上述分子表达无明显影响;3、RT-PCR及Western blot结果显示,新鲜分离单核细胞组成性表达MICA及MICB的转录体和蛋白,流式细胞检测发现单核细胞表面无或微弱地表达MICs分子;用MICs交叉反应性抗体行流式细胞检测,发现IFN-γ可以选择性上调PBMCs中单核细胞表面MICs表达;以MICA特异性及MICB特异性抗体行流式细胞术及Western blot检测,却发现IFN-γ刺激的单核细胞MICA及MICB表达均无明显上调,提示IFN-γ可能促进单核细胞某种未知的MIC分子表达;细胞因子TNF-α、IFN-α对单核细胞MICs表达无影响;4、IFN-γ刺激的单核细胞能促进异体NK细胞CD69及胞内IFN-γ表达,能增强NK细胞对K562细胞的杀伤效应;单核细胞的这种效应至少部分依赖于IFN-γ上调的MICs分子,因为用抗MICs抗体封闭或用细胞小室阻断细胞接触,可以显著地抑制NK细胞的活化;IFN-γ诱导上调的mIL-15能保护NK细胞免于MICs诱导的NKG2D受体下调;5、活化NK细胞分泌的IFN-γ能促进单核细胞表面MICs及mIL-15表达,单核细胞经活化的NK细胞培养上清作用后,能上调自体CD8~+CD28~-T细胞CD25表达并下调CD62L的表达,单核细胞表面上调表达的mIL-15有助于维持CD8~+CD28~-T细胞表面NKG2D的正常水平;6、IFN-γ刺激的慢性乙肝患者单核细胞与正常人NK细胞共培养,不能上调NK细胞的活化分子CD69及胞内IFN-γ的表达,也不能增强NK细胞对K562细胞的杀伤能力;对IFN-γ刺激后,15例健康志愿者及13例慢性乙肝患者单核细胞表面MIC及mIL-15的表达进行流式细胞检测,发现慢性乙肝患者单核细胞MICs及mIL-15阳性率低于健康志愿者(分别为21.10%±5.72%vs 42.61%±15.39%,及12.77%±4.31%vs 28.93%±5.77%),二者相比有显著性差异(p＜0.01)。
我们的实验结果表明,来源于淋巴细胞的IFN-γ对单核细胞有重要的免疫调节和修饰作用。IFN-γ促进单核细胞向成熟DCs分化;IFN-γ选择性上调PBMCs中单核细胞mIL-15及某种未知MIC分子(非MICA或MICB)的表达;单核细胞表面上调的MICs分子能够刺激NK细胞活化;活化NK细胞分泌的IFN-γ作用于单核细胞后,单核细胞又能依赖MICs分子共刺激CD8~+T细胞;单核细胞表面同时上调表达的mIL-15能够保护NK细胞或CD8~+T细胞免受MICs诱导的NKG2D受体下调;慢性乙肝患者单核细胞对IFN-γ诱导的MICs及mIL-15上调存在应答缺陷,这可能是慢性乙肝患者NK细胞功能低下及IFN-γ疗效不佳的潜在机制。总之,我们的研究描绘了以淋巴源性IFN-γ为信使,以NKG2D受体/配体为桥梁的单核细胞-NK/T细胞间的“对话机制”。
Natural killer(NK) cells and CD8~+ T cells composed the main effector cells of the native and adaptive immune response.When activated,they both exhibit the function as cytolysis and cytokines releasing;Among cytokines secreted by NK cells or T cells,IFN-γattracted more attention not only for it's direct anti-virus activities but also the immunoregulatory functions.
Activation-related immunoreceptor NKG2D is found expressed on NK cells,CD8~+ T cells,γδTCR~+ T cells,as well as the macrophages.Upon ligation with it's ligands, NKG2D initiate full activation signals for NK cells and macrophages,but co-stimulating signals for CD8~+ T cells in the presence of TCR stimulating.Among the NKG2D ligands, stress-inducible MHC class I chain related(MIC) molecules MICA and MICB are the first identified and also the best characterized.Cells expressing MIC molecules on their surface are susceptible to NK and T cell immunity.MICs has been observed up-regulated or induced on the surface of different cells in response to heat shock,oxidative stress, infection,and transformation.In normal humans,MICs is transcribed in keratinocytes, endothelial cells,fibroblasts,monocytes,epithelial cell lines and in gastrointestinal epithelial tissues.However it is not usually transcribed in T cells,B cells,and also NK cells. MICs protein has been found present at the cell surface of endothelial cells,fibroblasts,and epithelial cells in low level,or exist in the cytoplasm of monocytes,kerotinocytes and activated T cells.
Monocytes circulating in the blood stream are normally immunologicaly quiescent. However,under certain conditions they contribute to immune responses through differentiating into dendritic cells or secreting large amouts of cytokines.Recent reports even described a novel reciprocal activation between monocytes and lymphocytes;The cytokine IFN-γderived from NK cells or T cells,as well as the cell-cell contact seem to be the key factors involved in those cells cross-talk.In the regarding of the important role of NKG2D receptor in NK/T cell triggering and the role of NKG2D receptor/ligand system in cross-linking lymphocytes and antigen presenting cells(APCs),we presumably think NKG2D might mediate the interaction between monocytes and NK/T cells.
Although the immune response initiated by the T-cell response to viral antigens is fundamental for hepatitis B virus(HBV) clearance,NK cells are also essential for the initial control of HBV replication and the later induction of HBV-specific CTLs.The compromised function and decreased number of NK cells in chronic HBV infection has been observed,yet the underlied mechanism of NK cells functional defects still remain elusive.Additionally,IFN-γhas been proposed the most pivotal factors for host successive clearance of HBV,but exogenous IFN-γexhibits less efficience in the theapy of patients with chronic HBV infection.The precise reason is also not well understood.
To explore the role of NKG2D receptor/ligand system in the reciprocal interaction between NK/T cells and monocytes,and clarify the underlied mechanism causing functional impairement of NK cells and unresponsiveness to exogenous IFN-γin patients with chronic HBV infection,follows work were performed in this research:1.The morphologic and phenotypic changes of monocytes in the response of IFN-γ,TNF-α,and IFN-αstimulation were observed by microscope and flow cytometric analysis respectively; 2.The surface expression of MICs on PBMCs,isolated primary monocytes,as well as the monocytic cell line received various stimuli were examined by flow cytometry;3.RT-PCR and western blot were further used to determine the expression of MICA and MICB mRNA and protein in monocytes with or without IFN-γstimulation;4.IFN-γprestimulated monocytes were cocultured with allogenic NK cells,then NK cell activating marker of the surface CD69 and the intracellular IFN-γexpression were examined by flow cytometry,and the cytolytic capacity of NK cells against K562 cells was studied by ~(51)Cr-releasing assay;5. freshly isolated monocytes were subjected to treatment with the supernatant collected from the activated NK cells,monocytes surface expression of MICs and mIL-15 were analyzed by flow cytometry and then subjected to the coculture with CD8~+CD28~-T cells.CD8~+CD28~-T cells activating marker CD25 and CD62L were then detected by flow cytometry;6.The NKG2D expression level on NK/T cells were also assayed in the presence of anti-IL-15 antibodies or anti-MICs antibodies blocking after coculture with monocytes.7.The capacity of promoting normal NK cells activating by IFN-γ-prestimulated monocytes collected from patients with chronic HBV infection were assessed;and the property of MIC and mIL-15 induction in the response of IFN-γstimulation were also surveyed in 15 healthy donors and 13 patients with chronic HBV infection.
We demonstrated here that:1.After IFN-γstimulation,monocytes displayed the shape of fusiform or polygon and were more likely to adhere and cluster to form the distinct structure as "cell islet";IFN-αweakly promoted monocytes cluster and induced monocyte form lots of projections on the surface;TNF-αtreated monoctyes showed no visible morphologic changes;2.Both IFN-γand IFN-αinduced or up-regulated the surface expression of CD80,CD83,CD86,and HLA-DR on monocytes,concomitantly down-regulated the CD14 expression;IFN-γeven induced the CD1a expression on monocytes after 5 days stimulation;Monocytes cultured in vitro for 5 days in the presence of IFN-γchange their phenotype from CD14~+CD1a~-CD83~- to CD14~+CD1a~+CD83~+;TNF-αseemed can no impact monocyte phenotype;3.Freshly isolated monocytes displayed no or low level expression of MICs on the surface as assessed by flow cytometry;RT-PCR and western blotting revealed that both transcripts and protein of MICA and MICB exist in the lysates of freshly isolated monocytes.After IFN-γstimulation,MICs is exclusively induced or up-regulated on the surface of monocytes within PBMCs;Surprisingly,both MICA and MICB are not responsible for this up-regulation because neither anti-MICA nor anti-MICB mAB exhibited the enhanced positive staining,and this was confirmed by western blotting analyzing MICA and MICB protein expression in monocytes with or without IFN-γstimulation.4.IFN-γtreated monocytes enhanced IFN-γproduction,CD69 expression,and K562 cytolytic ability of NK cells.MICs-NKG2D interaction between NK and monocyte seem to be responsible for the NK activation,because mAB-mediated masking of MICs as well as inhibition of cell-to-cell contact using transwell insert significantly abolished NK cell activation.Meanwhile,IFN-γsecreted by activated NK cells also conferred monocytes the capacity of activating CD8~+CD28~- T cells in the presence of anti-CD3 stimulation;5. The enhanced expression of MICs was associated with the up-regulation of membrane-bound IL-15(mIL-15) expression on monocytes,which elicit the role of preventing NK cells or CD8~+CD28~- T cells from MICs-induced NKG2D down-modulation in the contact with monocytes;6.Finally,monocytes recovered from chronic HBV-infected patients showed defects in MICs and mIL-15 surface induction and impaired ability to activate NK cells in response to IFN-γstimulation.
Based on these findings we can draw a conclusion that lymphocytes-derived IFN-γmay exerts it's immunoregulatory role through driving monocytes differentiate to mature dendritic cells(DCs) and up-regulating a novel unknown MIC molecule and mIL-15 expression on monocytes;The up-regulated MIC and mIL-15 were then synergistically enhance NK/T cells activities.The defects of MIC and mIL-15 induction on monocyte might contribute to NK cells functional compromise in chronic hepatitis B virus infection.
NKG2D是一种表达于NK细胞、巨噬细胞、CD8~+T细胞及γδTCR~+T细胞表面的活化受体,由NKG2D启动的信号可直接活化NK细胞和巨噬细胞;对于T细胞,NKG2D提供重要的共刺激信号。MHC-I类链相关分子(MICs)是最早被发现且研究较充分的NKG2D受体的配体。MICs定位于HLA-I类基因区,在MICA-MICG七个成员中,目前认为MICA及MICB是能够被转录翻译的功能基因。作为一种应激的标记分子,MICs广泛表达于处于热休克、氧化应激、感染及恶变的细胞表面,当它被NK/T细胞表面的NKG2D受体识别并结合后,即可启动NK细胞或T细胞介导的免疫应答,最终导致这些“异常”细胞被清除。MICs分子也低水平表达于正常肠上皮细胞、某些内皮细胞及成纤维细胞表面;在单核细胞、某些角质细胞及活化的T细胞胞浆内,也检测到MIC蛋白的表达。正常细胞表面低水平或阴性表达MICs分子,可能是机体的一种自我保护机制。
单核细胞是单核-巨噬系统的主要成份。体内单核细胞正常情况下处于免疫静息状态,但在适宜的条件作用下,它可以通过转化为DCs或者分泌大量细胞因子来参与或调节免疫应答。最近研究发现,单核细胞与NK细胞或T细胞之间存在着对话机制,并且淋巴细胞产生的IFN-γ及细胞间的直接接触可能是介导单核细胞与淋巴细胞相互作用的关键环节。但对于IFN-γ在调节单核细胞与淋巴细胞之间对话的具体分子机制,目前仍不清楚。考虑到NKG2D在调控淋巴细胞活化及其在天然免疫及适应性免疫应答之间的重要“桥梁”作用,我们猜测NKG2D受体/配体系统极可能也参与了IFN-γ介导的淋巴细胞/单核细胞之间的对话。
虽然HBV特异性T细胞应答是机体清除HBV的关键,但NK细胞在HBV感染早期控制病毒复制及辅助HBV特异性CTLs产生方面也扮演重要角色。HBV慢性感染常常伴有NK细胞数量和功能的下降,另一方面,慢性乙肝患者对外源性IFN-γ治疗呈低反应性。HBV慢性感染的NK细胞功能受损是否与单核细胞与NK细胞间交互互作用障碍有关?IFN-γ对慢性乙肝患者单核细胞是否有正常的免疫调节和修饰作用?也是有待回答的问题。
基于以上研究背景和存在问题,我们从以下方面进行了相关研究:1、从健康志愿者PBMCs中分选单核细胞,采用流式细胞术和形态观测的方法检测了细胞因子IFN-γ、TNF-α、IFN-α刺激前后单核细胞形态学变化和有关表型分子CD14、CD1a、CD80、CD83、CD86、HLA-DR的表达变化;2、流式细胞术检测细胞因子IFN-γ、TNF-α、IFN-α对正常PBMCs、分选的原代单核细胞以及单核细胞系U937、THP-1表面MIC表达的影响;3、采用RT-PCR及Western blot检测了IFN-γ刺激前后单核细胞MICs的表达;4、将IFN-γ刺激的单核细胞与异体NK细胞进行共培养,采用流式细胞术检测NK细胞活化标志分子CD69及胞内IFN-γ的表达,同时以~(51)Cr释放试验分析了NK细胞对其靶细胞K562细胞的细胞毒效应,观察单核细胞表面MICs分子及膜结合型IL-15(mIL-15)在NK细胞活化及NKG2D受体维持中的作用;5、采用磁珠活化NK细胞,收集活化NK细胞培养上清,与单核细胞进行培养后,再将单核细胞与自体CD8~+CD28~-T细胞进行共培养,流式细胞术检测单核细胞MICs及T细胞活化相关分子CD25、CD62L的表达;6、采用流式细胞术及~(51)Cr释放试验检测了IFN-γ刺激的慢性乙肝患者单核细胞与正常人NK细胞共培养后,NK细胞的活化分子CD69及胞内IFN-γ的表达,以及NK细胞对K562细胞的杀伤能力;7、流式细胞检测并比较了IFN-γ刺激后,15例健康志愿者及13例慢性乙肝患者单核细胞表面MICs及mIL-15的表达差异。
我们的结果发现:1、IFN-γ能促进单核细胞粘附聚集,单核细胞簇集形成独特的“细胞小岛”样结构,IFN-γ刺激的单核细胞呈梭形或多角形,表面有突起形成;IFN-α有较微弱的促进单核细胞簇集的作用,IFN-α刺激的单核细胞形成较多突起,形似星形;TNF-α对单核细胞形态无明显影响;2、IFN-γ刺激5 day后,单核细胞同时具有DCs及单核细胞表型特征,体现为由CD14~+CD1a~-CD83~-转变为CD14~+CD1a~+CD83~+,但CD14表达水平明显下降,IFN-γ还能促进单核细胞CD80、CD86及HLA-DR的表达;IFN-α也能促进单核细胞CD80、CD83、CD86及HLA-DR的表达,能下调CD14表达,但不能上调CD1a表达,上调CD83的能力较弱;TNF-α对上述分子表达无明显影响;3、RT-PCR及Western blot结果显示,新鲜分离单核细胞组成性表达MICA及MICB的转录体和蛋白,流式细胞检测发现单核细胞表面无或微弱地表达MICs分子;用MICs交叉反应性抗体行流式细胞检测,发现IFN-γ可以选择性上调PBMCs中单核细胞表面MICs表达;以MICA特异性及MICB特异性抗体行流式细胞术及Western blot检测,却发现IFN-γ刺激的单核细胞MICA及MICB表达均无明显上调,提示IFN-γ可能促进单核细胞某种未知的MIC分子表达;细胞因子TNF-α、IFN-α对单核细胞MICs表达无影响;4、IFN-γ刺激的单核细胞能促进异体NK细胞CD69及胞内IFN-γ表达,能增强NK细胞对K562细胞的杀伤效应;单核细胞的这种效应至少部分依赖于IFN-γ上调的MICs分子,因为用抗MICs抗体封闭或用细胞小室阻断细胞接触,可以显著地抑制NK细胞的活化;IFN-γ诱导上调的mIL-15能保护NK细胞免于MICs诱导的NKG2D受体下调;5、活化NK细胞分泌的IFN-γ能促进单核细胞表面MICs及mIL-15表达,单核细胞经活化的NK细胞培养上清作用后,能上调自体CD8~+CD28~-T细胞CD25表达并下调CD62L的表达,单核细胞表面上调表达的mIL-15有助于维持CD8~+CD28~-T细胞表面NKG2D的正常水平;6、IFN-γ刺激的慢性乙肝患者单核细胞与正常人NK细胞共培养,不能上调NK细胞的活化分子CD69及胞内IFN-γ的表达,也不能增强NK细胞对K562细胞的杀伤能力;对IFN-γ刺激后,15例健康志愿者及13例慢性乙肝患者单核细胞表面MIC及mIL-15的表达进行流式细胞检测,发现慢性乙肝患者单核细胞MICs及mIL-15阳性率低于健康志愿者(分别为21.10%±5.72%vs 42.61%±15.39%,及12.77%±4.31%vs 28.93%±5.77%),二者相比有显著性差异(p＜0.01)。
我们的实验结果表明,来源于淋巴细胞的IFN-γ对单核细胞有重要的免疫调节和修饰作用。IFN-γ促进单核细胞向成熟DCs分化;IFN-γ选择性上调PBMCs中单核细胞mIL-15及某种未知MIC分子(非MICA或MICB)的表达;单核细胞表面上调的MICs分子能够刺激NK细胞活化;活化NK细胞分泌的IFN-γ作用于单核细胞后,单核细胞又能依赖MICs分子共刺激CD8~+T细胞;单核细胞表面同时上调表达的mIL-15能够保护NK细胞或CD8~+T细胞免受MICs诱导的NKG2D受体下调;慢性乙肝患者单核细胞对IFN-γ诱导的MICs及mIL-15上调存在应答缺陷,这可能是慢性乙肝患者NK细胞功能低下及IFN-γ疗效不佳的潜在机制。总之,我们的研究描绘了以淋巴源性IFN-γ为信使,以NKG2D受体/配体为桥梁的单核细胞-NK/T细胞间的“对话机制”。
Natural killer(NK) cells and CD8~+ T cells composed the main effector cells of the native and adaptive immune response.When activated,they both exhibit the function as cytolysis and cytokines releasing;Among cytokines secreted by NK cells or T cells,IFN-γattracted more attention not only for it's direct anti-virus activities but also the immunoregulatory functions.
Activation-related immunoreceptor NKG2D is found expressed on NK cells,CD8~+ T cells,γδTCR~+ T cells,as well as the macrophages.Upon ligation with it's ligands, NKG2D initiate full activation signals for NK cells and macrophages,but co-stimulating signals for CD8~+ T cells in the presence of TCR stimulating.Among the NKG2D ligands, stress-inducible MHC class I chain related(MIC) molecules MICA and MICB are the first identified and also the best characterized.Cells expressing MIC molecules on their surface are susceptible to NK and T cell immunity.MICs has been observed up-regulated or induced on the surface of different cells in response to heat shock,oxidative stress, infection,and transformation.In normal humans,MICs is transcribed in keratinocytes, endothelial cells,fibroblasts,monocytes,epithelial cell lines and in gastrointestinal epithelial tissues.However it is not usually transcribed in T cells,B cells,and also NK cells. MICs protein has been found present at the cell surface of endothelial cells,fibroblasts,and epithelial cells in low level,or exist in the cytoplasm of monocytes,kerotinocytes and activated T cells.
Monocytes circulating in the blood stream are normally immunologicaly quiescent. However,under certain conditions they contribute to immune responses through differentiating into dendritic cells or secreting large amouts of cytokines.Recent reports even described a novel reciprocal activation between monocytes and lymphocytes;The cytokine IFN-γderived from NK cells or T cells,as well as the cell-cell contact seem to be the key factors involved in those cells cross-talk.In the regarding of the important role of NKG2D receptor in NK/T cell triggering and the role of NKG2D receptor/ligand system in cross-linking lymphocytes and antigen presenting cells(APCs),we presumably think NKG2D might mediate the interaction between monocytes and NK/T cells.
Although the immune response initiated by the T-cell response to viral antigens is fundamental for hepatitis B virus(HBV) clearance,NK cells are also essential for the initial control of HBV replication and the later induction of HBV-specific CTLs.The compromised function and decreased number of NK cells in chronic HBV infection has been observed,yet the underlied mechanism of NK cells functional defects still remain elusive.Additionally,IFN-γhas been proposed the most pivotal factors for host successive clearance of HBV,but exogenous IFN-γexhibits less efficience in the theapy of patients with chronic HBV infection.The precise reason is also not well understood.
To explore the role of NKG2D receptor/ligand system in the reciprocal interaction between NK/T cells and monocytes,and clarify the underlied mechanism causing functional impairement of NK cells and unresponsiveness to exogenous IFN-γin patients with chronic HBV infection,follows work were performed in this research:1.The morphologic and phenotypic changes of monocytes in the response of IFN-γ,TNF-α,and IFN-αstimulation were observed by microscope and flow cytometric analysis respectively; 2.The surface expression of MICs on PBMCs,isolated primary monocytes,as well as the monocytic cell line received various stimuli were examined by flow cytometry;3.RT-PCR and western blot were further used to determine the expression of MICA and MICB mRNA and protein in monocytes with or without IFN-γstimulation;4.IFN-γprestimulated monocytes were cocultured with allogenic NK cells,then NK cell activating marker of the surface CD69 and the intracellular IFN-γexpression were examined by flow cytometry,and the cytolytic capacity of NK cells against K562 cells was studied by ~(51)Cr-releasing assay;5. freshly isolated monocytes were subjected to treatment with the supernatant collected from the activated NK cells,monocytes surface expression of MICs and mIL-15 were analyzed by flow cytometry and then subjected to the coculture with CD8~+CD28~-T cells.CD8~+CD28~-T cells activating marker CD25 and CD62L were then detected by flow cytometry;6.The NKG2D expression level on NK/T cells were also assayed in the presence of anti-IL-15 antibodies or anti-MICs antibodies blocking after coculture with monocytes.7.The capacity of promoting normal NK cells activating by IFN-γ-prestimulated monocytes collected from patients with chronic HBV infection were assessed;and the property of MIC and mIL-15 induction in the response of IFN-γstimulation were also surveyed in 15 healthy donors and 13 patients with chronic HBV infection.
We demonstrated here that:1.After IFN-γstimulation,monocytes displayed the shape of fusiform or polygon and were more likely to adhere and cluster to form the distinct structure as "cell islet";IFN-αweakly promoted monocytes cluster and induced monocyte form lots of projections on the surface;TNF-αtreated monoctyes showed no visible morphologic changes;2.Both IFN-γand IFN-αinduced or up-regulated the surface expression of CD80,CD83,CD86,and HLA-DR on monocytes,concomitantly down-regulated the CD14 expression;IFN-γeven induced the CD1a expression on monocytes after 5 days stimulation;Monocytes cultured in vitro for 5 days in the presence of IFN-γchange their phenotype from CD14~+CD1a~-CD83~- to CD14~+CD1a~+CD83~+;TNF-αseemed can no impact monocyte phenotype;3.Freshly isolated monocytes displayed no or low level expression of MICs on the surface as assessed by flow cytometry;RT-PCR and western blotting revealed that both transcripts and protein of MICA and MICB exist in the lysates of freshly isolated monocytes.After IFN-γstimulation,MICs is exclusively induced or up-regulated on the surface of monocytes within PBMCs;Surprisingly,both MICA and MICB are not responsible for this up-regulation because neither anti-MICA nor anti-MICB mAB exhibited the enhanced positive staining,and this was confirmed by western blotting analyzing MICA and MICB protein expression in monocytes with or without IFN-γstimulation.4.IFN-γtreated monocytes enhanced IFN-γproduction,CD69 expression,and K562 cytolytic ability of NK cells.MICs-NKG2D interaction between NK and monocyte seem to be responsible for the NK activation,because mAB-mediated masking of MICs as well as inhibition of cell-to-cell contact using transwell insert significantly abolished NK cell activation.Meanwhile,IFN-γsecreted by activated NK cells also conferred monocytes the capacity of activating CD8~+CD28~- T cells in the presence of anti-CD3 stimulation;5. The enhanced expression of MICs was associated with the up-regulation of membrane-bound IL-15(mIL-15) expression on monocytes,which elicit the role of preventing NK cells or CD8~+CD28~- T cells from MICs-induced NKG2D down-modulation in the contact with monocytes;6.Finally,monocytes recovered from chronic HBV-infected patients showed defects in MICs and mIL-15 surface induction and impaired ability to activate NK cells in response to IFN-γstimulation.
Based on these findings we can draw a conclusion that lymphocytes-derived IFN-γmay exerts it's immunoregulatory role through driving monocytes differentiate to mature dendritic cells(DCs) and up-regulating a novel unknown MIC molecule and mIL-15 expression on monocytes;The up-regulated MIC and mIL-15 were then synergistically enhance NK/T cells activities.The defects of MIC and mIL-15 induction on monocyte might contribute to NK cells functional compromise in chronic hepatitis B virus infection.
引文
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