CD4~+NKG2D~+T细胞与单核细胞相互活化参与系统性红斑狼疮疾病作用及机制研究
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摘要
NKG2D为NK细胞活化性受体,近来研究发现可表达于多种免疫细胞,如CD8+αβT细胞、γδT细胞以及NKT细胞上,不表达在正常CD4+ T细胞上,但是可以在TNF-α和IL-15作用下诱导表达。NKG2D的配体包括MHC I类链相关分子家族(MICA/B)和人巨细胞病毒蛋白UL16的结合蛋白(ULBP)家族。其中,MICA/B表达在正常肠道上皮表面,在压力诱导下,如病毒或细菌感染、恶性转化时,可以在感染细胞或肿瘤细胞上表达。上调的配体的表达可以与NK细胞、CD8+ T细胞细胞表面NKG2D活化受体相互识别,活化NK细胞并为CD8+ T细胞提供共刺激信号,从而发挥免疫防御和免疫监视的功能。但是,MIC/NKG2D的相互作用也能够降低TCR信号活化的阈值,因此,这种受体配体的相互识别也参与了自身免疫性疾病的发生发展,甚至促进了自身免疫性疾病的恶性转归。已有文献报道MIC/NKG2D配体受体作用参与了类风湿关节炎、HTLV-1相关性神经系统疾病和Crohn’s氏肠炎。其机制可能是自身免疫性疾病患者体内血清高水平的IL-15或TNF-α,导致了NKG2D受体的上调表达,同时,患者在滑膜细胞或肠道上皮细胞的NKG2D配体亦高表达,因此NKG2D与其配体相互识别并活化了自身反应性淋巴细胞从而导致了疾病的发生发展。在类风湿关节炎中首次发现了患者外周血中存在CD4+NKG2D+ T淋巴细胞,该群淋巴细胞缺失CD28的表达,并且可以分泌穿孔素和颗粒酶B,在疾病中扮演了自身反应性T细胞的角色。之后在Crohn’s氏肠炎及Wegener's肉芽肿中也发现了这群特殊的淋巴细胞亚群。以上内容提示我们NKG2D/MIC参与了自身免疫病中病程。
系统性红斑狼疮(Systemic lupus erythematosus ,SLE)是一种以多种自身抗体产生及严重免疫紊乱的全身多系统、多器官受累为特征的自身免疫性疾病。患者肾脏、皮肤、血管甚至中枢神经受累,其病情呈反复发作与缓解交替过程。多种免疫紊乱因素参与其中,包括多种自身抗体的产生,血清细胞因子紊乱,IFN-γ的参与以及免疫调节功能缺陷等。IFN-γ由淋巴细胞分泌产生,在免疫防御方面如杀伤病原微生物感染的靶细胞起到重要的作用,同时在免疫调节方面也发挥了重要作用。我们以前的研究成果已经报道了IFN-γ参与了单核细胞与NK的相互活化作用,诱导了单核细胞表面MIC和膜型IL-15的表达,从而使得单核与NK可以相互识别相互对话。由于IL-15可以诱导CD4+ T细胞上NKG2D受体的表达,记忆SLE患者体内存在大量异常增生的自身反应性T淋巴细胞,我们推测,SLE患者血清高水平的IFN-γ在上调单核细胞表面MIC和膜型IL-15的表达后,膜型IL-15又可以诱导CD4+ T细胞上NKG2D的表达,继而单核细胞与CD4+ T细胞通过MIC/NKG2D作用相互识别,产生单核细胞与CD4+ T淋巴细胞的相互对话。那么,SLE患者外周血是否存在CD4+NKG2D+ T细胞呢,这群细胞是否具有自身反应性,其异常活化的机制又是什么呢?
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、多色流式技术检测并比较了20例SLE患者与20例健康志愿者外周血CD4+NKG2D+ T频率以及单核细胞表面MICs及mIL-15的表达差异了,并分析了单核细胞MICs表达率与SLEDAI评分的相关性;2、ELISA检测并比较了20例SLE患者与20例健康志愿者血清IFN-γ、IFN-α的水平,并检测了IFN-γ、IFN-α对分选的原代单核细胞以及单核细胞系U937、THP-1表面MICs表达的影响,分析了血清IFN-γ水平与单核细胞MICs表达率的相关性;3、共培养实验检测并比较了SLE患者与健康对照者的单核细胞诱导健康对照者CD4+ T细胞NKG2D的表达的差异,观察了阻断单核细胞表面膜型IL-15后NKG2D表达的差异以及观察了IFN-γ刺激的正常人单核细胞在不同细胞比例、不同培养时间下,对CD4+ T细胞NKG2D诱导表达的差异;4、体外共培养SLE患者单核细胞与健康对照者CD4+ T细胞,并采用流式细胞术检测CD4+ T细胞活化标志分子CD25、CD69及胞内IFN-γ的表达,观察单核细胞表面MICs分子及膜结合型IL-15(mIL-15)在CD4+ T细胞活化中的作用;5、采用流式细胞术检测了IFN-γ刺激与未刺激的正常人单核细胞与CD4+ T细胞共培养后,CD4+ T细胞的活化分子CD25、CD69及胞内IFN-γ的表达,以及穿孔素、颗粒酶的表达,并采用ELISA检测了培养上清中Th1及Th2代表性细胞因子IFN-γ和IL-4的分泌情况,以transwell及单抗阻断实验明确了细胞直接接触、单核细胞表面MICs分子和膜型IL-15(mIL-15)在CD4+ T细胞活化中的作用;6、采用CCK-8掺入法检测了IFN-γ刺激与未刺激的正常人单核细胞与CD4+ T细胞共培养后,CD4+ T细胞增殖的不同,并观察了细胞直接接触、单核细胞表面MICs分子和膜型IL-15(mIL-15)在促进CD4+ T细胞增殖中的作用。
我们的结果发现:1、SLE患者外周血存在异常增生的CD4+NKG2D+ T细胞和MIC+单核细胞:病人CD4+ T细胞NKG2D阳性率为20.1±7.3%,健康志愿者CD4+ T细胞NKG2D阳性率为3.4±1.5%,单核细胞MICs及mIL-15的阳性率分别为37±18.1%和36±7.3%,而健康志愿者单核细胞MICs及mIL-15的阳性率为7.2±2.4%和7.6±2. 5%。SLE患者与健康志愿者NKG2D、MICs及mIL-15阳性率比较前者都要高于后者,二者比较有差异显著(p<0.01),且SLE患者单核细胞MIC分子表达与SLEDAI评分正相关;2、SLE患者血清IFN-γ的异常升高导致单核细胞MICs、mIL-15的显著上调:SLE患者血清IFN-γ和IFN-α水平与健康对照组相比有显著性差异,其中IFN-γ在SLE患者为150.3-669.5 pg/mL, mean 429.7±145 pg/mL) (健康对照为18.8-88.2 pg/mL, mean 73.8±18.9pg/mL),与单核细胞MICs表达率成正相关,IFN-α在SLE患者为198.3-489.2pg/mL, mean319±86.1pg/mL) (健康对照为58.8-322.2 pg/mL, mean151.9±78.5pg/mL)。流式细胞检测发现正常单核细胞表面无或微弱地表达MICs分子,发现IFN-γ而非IFN-α可以选择性上调原代单核细胞及单核细胞系表面MICs表达;3、SLE患者来源的单核细胞可以通过膜型IL-15诱导CD4+ T细胞NKG2D受体的表达,并能够通过MIC/NKG2D相互作用活化CD4+ T细胞,上调活化标志CD25、CD69及胞内IFN-γ的表达,细胞直接接触、mIL-15及NKG2D/MIC参与了CD4+ T细胞的活化;4、SLE患者的单核细胞促进CD4+ NKG2D+ T细胞的活化需要异常升高的IFN-γ的微环境:体外IFN-γ刺激的单核细胞可以通过mIL-15依赖的、NKG2D/MICs介导的方式活化CD4+ T细胞,并使得CD4+ T细胞Th1极化,分泌大量穿孔素和颗粒酶,同时还能够促进CD4+ T细胞的增殖;5、活化CD4+ T细胞分泌的IFN-γ能促进单核细胞表面MICs及mIL-15表达,单核细胞表面上调表达的mIL-15有助于维持CD4+ T细胞表面NKG2D的正常水平,继而通过NKG2D/MIC的相互作用又可相互活化,这种crosstalk即可能参与了SLE疾病的进程及恶化。
NKG2D is a key homodimeric activation receptor expressed on the cell surface of almost all NK cells,γδcells, some cytolytic CD8+ T cells and NKT cells, and normally absent on CD4+ T cells but can be induced by TNF-αand IL-15. Several ligands that bind to NKG2D are members of the MHC class I chain-related family, MICA and MICB. Normally, MICA/B have a restricted tissue distribution in intestinal epithelium, and can be stress-induced molecules by viral and bacterial infections, malignant transformation, and proliferation acting as danger signals to alert NK cells and CD8+ T lymphocytes through engagement of the NKG2D activating receptor. In addition, the MIC/NKG2D interaction may lower the threshold of TCR activation by specific antigen and thus trigger or exacerbate an autoimmune response. Data from the literature strongly support the idea that the NKG2D-MIC activation pathway participates in the development of immune mediated disorders. Recently there had been some reports about a novel subset of NKG2D+ CD4+ T cells in some autoimmune disease such as rheumatoid arthritis, HTLV-1-associated neurologic disease, and Crohn’s diseases. Upregulation of MICA/B ligands and high level of IL-15/ TNF-αactivate the effector CD4+ T cells and induce the expression of NKG2D. This subset T cells show the deficiency of the surface marker of CD28 and can secret perforin and granzyme B acting as cytolytic and autoreactive T cells. Later, some groups have been reported that anomalous NKG2D expression on circulating CD4+ T cells in patients with Wegener's granulomatosis .
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the deposition of immune complexes with an inflammatory/necrotic phenomenon in different tissues, mainly kidney, skin, blood vessels and central nervous system. Multiple immune abnormalities are characteristic of this condition, including the synthesis of different autoantibodies, enhanced synthesis of IFN-γand defective immunoregulatory function. IFN-γis secreted by lymphoctyes in vivo and plays an essential role in immunologic defence even in immunoregulation. We and others previous study demonstrated that IFN-γparticipate in the crosstalk between NK cells and monocytes by inducing or enhancing the expression of MIC and mIL-15 on monocytes. Considering that IL-15 can induce NKG2D expression on CD4+ T cells, we wonder whether monocytes in patients with SLE aberrantly displayed enhanced expression of MIC and mIL-15 on the surface due to the increased concentration of serum IFN-γ. If this is true, we want to know whether there is a subpopulation of CD4+ T cells expressing NKG2D existing in SLE patients, which maybe induced by mIL-15 on CD14+ monocytes. It is of great interest to further dissect the mechanisms of NKG2D/MIC interaction during the crosstalk of CD4+ T cells and CD14+ monocytes.
Thus, in this study, we investigate the NKG2D receptor expression on CD4+ T cells as well as MIC and mIL-15 expression on CD14+ monocytes in SLE patients. The methods is as follows:1. We detected and analyze the frequency of CD4+NKG2D+ T cells and MIC+ monocytes and the expression of mIL-15 between SLE patients and normal control. Also, we analyzed whether there are correlation between the frequency of MIC+ monocytes and SLEDAI.2. We detected the concentration of IFN-γand IFN-αin sera of SLE patients and normal controls.Then we investigated the effects of IFN-γ, IFN-αon MIC expression of primary monocytes and monocytic cell lines, for example, THP-1 and U937. We also nalyzed whether there are correlation between the concentration of IFN-γin patients sera and MIC+ monocytes.3. With cocultue system, we investigated the effect of monocytes derived from SLE patients and normal controls on the induction of NKG2D receptor expression on CD4+ T cells. Furthermore, we decteted this effect of IFN-γ-treated monocytes on NKG2D expression in different time point and different cell ratio. In some expriments, anti-IL-15 antibodies were adding to the coculture system.4. We detected the activatory marker of CD25 and CD69 and IFN-γproduction of the cocultured CD4+ T cells. In some expriments, anti-IL-15 antibodies,anti-MICs antibodies and transwell were adding to the coculture system.5.We investigated the effect of IL-15 and NKG2D/MIC on the cocultured CD4+ T cells. We detected activatory marker of CD25 and CD69 , IFN-γlevel either using ELISA and intracellular cytokines staining , and the production of perforin and granzyme B in the absence or presence of transwell, anti-IL-15 Abs and anti-MIC Abs. In addition, we observed the proliferatin of cocultred CD4+ T cells by using Cell Counting Kit-8 ( CCK-8)
The results are as follows:1. In normal controls, the NKG2D expression was nearly not observed on CD4+ T PBLs (1.2-8.3%, mean 3.4±1.5%) compared with 8-33% (mean 20.1±7.3%) in SLE. The expression of MIC on monocytes is (5–12%, mean7.2±2.4%). In normal controls compared with (11–76%, mean 37±18.1%) in patients. When analyzing the expression of membrane bound IL-15 (mIL-15) on monocytes, we found that mIL-15 expression of CD14+ monocytes in SLE patients (25-48%, mean 36±7.3%) was significantly higher than those in normal controls (5-13%, mean 7.6±2. 5%) .The expression of MIC on monocytes is significantly correlated with SLEDAI. 2. Elevated serum IFN-γhas been found in SLE patients. Our results showed that the concentration of IFN-γin SLE patients (150.3-669.5 pg/mL, mean 429.7±145 pg/mL) was remarkablely higher than those in normal controls (18.8-88.2 pg/mL, mean 73.8±18.9pg/mL),while IFN-α(198.3-489.2pg/mL, mean319±86.1pg/mL) in patients compared with (58.8-322.2 pg/mL, mean151.9±78.5pg/mL) in normal controls. .The concentration of IFN-γin patients is significantly correlated with expression of MIC on monocytes. IFN-γcan upregulated the expression of MIC on primary monocytes and monocytic cell lines. 3. IFN-γpretreated monocytes or freshly isolated monocytes induced NKG2D expression on CD4+ T cells, and can activate CD4+ T Cells via NKG2D/MIC requiring IL-15. 4. Monocytes expressing MIC and mIL-15 promote NKG2D+CD4+ T cells activation via NKG2D/MIC interaction in a IFN-γ-dependent manner.5. The activated CD4+ T cells produced IFN-γand upregulated the MIC and mIL-15 on monocytes. Hence in a feedback , CD4+ T cells and monocytes can crosstalk in IFN-γand mIL-15 dependent manner via NKG2D/MIC interation and activate reciprocally. This crosstalk maybe contribute the exacerbation of the pathogenesis of SLE.
系统性红斑狼疮(Systemic lupus erythematosus ,SLE)是一种以多种自身抗体产生及严重免疫紊乱的全身多系统、多器官受累为特征的自身免疫性疾病。患者肾脏、皮肤、血管甚至中枢神经受累,其病情呈反复发作与缓解交替过程。多种免疫紊乱因素参与其中,包括多种自身抗体的产生,血清细胞因子紊乱,IFN-γ的参与以及免疫调节功能缺陷等。IFN-γ由淋巴细胞分泌产生,在免疫防御方面如杀伤病原微生物感染的靶细胞起到重要的作用,同时在免疫调节方面也发挥了重要作用。我们以前的研究成果已经报道了IFN-γ参与了单核细胞与NK的相互活化作用,诱导了单核细胞表面MIC和膜型IL-15的表达,从而使得单核与NK可以相互识别相互对话。由于IL-15可以诱导CD4+ T细胞上NKG2D受体的表达,记忆SLE患者体内存在大量异常增生的自身反应性T淋巴细胞,我们推测,SLE患者血清高水平的IFN-γ在上调单核细胞表面MIC和膜型IL-15的表达后,膜型IL-15又可以诱导CD4+ T细胞上NKG2D的表达,继而单核细胞与CD4+ T细胞通过MIC/NKG2D作用相互识别,产生单核细胞与CD4+ T淋巴细胞的相互对话。那么,SLE患者外周血是否存在CD4+NKG2D+ T细胞呢,这群细胞是否具有自身反应性,其异常活化的机制又是什么呢?
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、多色流式技术检测并比较了20例SLE患者与20例健康志愿者外周血CD4+NKG2D+ T频率以及单核细胞表面MICs及mIL-15的表达差异了,并分析了单核细胞MICs表达率与SLEDAI评分的相关性;2、ELISA检测并比较了20例SLE患者与20例健康志愿者血清IFN-γ、IFN-α的水平,并检测了IFN-γ、IFN-α对分选的原代单核细胞以及单核细胞系U937、THP-1表面MICs表达的影响,分析了血清IFN-γ水平与单核细胞MICs表达率的相关性;3、共培养实验检测并比较了SLE患者与健康对照者的单核细胞诱导健康对照者CD4+ T细胞NKG2D的表达的差异,观察了阻断单核细胞表面膜型IL-15后NKG2D表达的差异以及观察了IFN-γ刺激的正常人单核细胞在不同细胞比例、不同培养时间下,对CD4+ T细胞NKG2D诱导表达的差异;4、体外共培养SLE患者单核细胞与健康对照者CD4+ T细胞,并采用流式细胞术检测CD4+ T细胞活化标志分子CD25、CD69及胞内IFN-γ的表达,观察单核细胞表面MICs分子及膜结合型IL-15(mIL-15)在CD4+ T细胞活化中的作用;5、采用流式细胞术检测了IFN-γ刺激与未刺激的正常人单核细胞与CD4+ T细胞共培养后,CD4+ T细胞的活化分子CD25、CD69及胞内IFN-γ的表达,以及穿孔素、颗粒酶的表达,并采用ELISA检测了培养上清中Th1及Th2代表性细胞因子IFN-γ和IL-4的分泌情况,以transwell及单抗阻断实验明确了细胞直接接触、单核细胞表面MICs分子和膜型IL-15(mIL-15)在CD4+ T细胞活化中的作用;6、采用CCK-8掺入法检测了IFN-γ刺激与未刺激的正常人单核细胞与CD4+ T细胞共培养后,CD4+ T细胞增殖的不同,并观察了细胞直接接触、单核细胞表面MICs分子和膜型IL-15(mIL-15)在促进CD4+ T细胞增殖中的作用。
我们的结果发现:1、SLE患者外周血存在异常增生的CD4+NKG2D+ T细胞和MIC+单核细胞:病人CD4+ T细胞NKG2D阳性率为20.1±7.3%,健康志愿者CD4+ T细胞NKG2D阳性率为3.4±1.5%,单核细胞MICs及mIL-15的阳性率分别为37±18.1%和36±7.3%,而健康志愿者单核细胞MICs及mIL-15的阳性率为7.2±2.4%和7.6±2. 5%。SLE患者与健康志愿者NKG2D、MICs及mIL-15阳性率比较前者都要高于后者,二者比较有差异显著(p<0.01),且SLE患者单核细胞MIC分子表达与SLEDAI评分正相关;2、SLE患者血清IFN-γ的异常升高导致单核细胞MICs、mIL-15的显著上调:SLE患者血清IFN-γ和IFN-α水平与健康对照组相比有显著性差异,其中IFN-γ在SLE患者为150.3-669.5 pg/mL, mean 429.7±145 pg/mL) (健康对照为18.8-88.2 pg/mL, mean 73.8±18.9pg/mL),与单核细胞MICs表达率成正相关,IFN-α在SLE患者为198.3-489.2pg/mL, mean319±86.1pg/mL) (健康对照为58.8-322.2 pg/mL, mean151.9±78.5pg/mL)。流式细胞检测发现正常单核细胞表面无或微弱地表达MICs分子,发现IFN-γ而非IFN-α可以选择性上调原代单核细胞及单核细胞系表面MICs表达;3、SLE患者来源的单核细胞可以通过膜型IL-15诱导CD4+ T细胞NKG2D受体的表达,并能够通过MIC/NKG2D相互作用活化CD4+ T细胞,上调活化标志CD25、CD69及胞内IFN-γ的表达,细胞直接接触、mIL-15及NKG2D/MIC参与了CD4+ T细胞的活化;4、SLE患者的单核细胞促进CD4+ NKG2D+ T细胞的活化需要异常升高的IFN-γ的微环境:体外IFN-γ刺激的单核细胞可以通过mIL-15依赖的、NKG2D/MICs介导的方式活化CD4+ T细胞,并使得CD4+ T细胞Th1极化,分泌大量穿孔素和颗粒酶,同时还能够促进CD4+ T细胞的增殖;5、活化CD4+ T细胞分泌的IFN-γ能促进单核细胞表面MICs及mIL-15表达,单核细胞表面上调表达的mIL-15有助于维持CD4+ T细胞表面NKG2D的正常水平,继而通过NKG2D/MIC的相互作用又可相互活化,这种crosstalk即可能参与了SLE疾病的进程及恶化。
NKG2D is a key homodimeric activation receptor expressed on the cell surface of almost all NK cells,γδcells, some cytolytic CD8+ T cells and NKT cells, and normally absent on CD4+ T cells but can be induced by TNF-αand IL-15. Several ligands that bind to NKG2D are members of the MHC class I chain-related family, MICA and MICB. Normally, MICA/B have a restricted tissue distribution in intestinal epithelium, and can be stress-induced molecules by viral and bacterial infections, malignant transformation, and proliferation acting as danger signals to alert NK cells and CD8+ T lymphocytes through engagement of the NKG2D activating receptor. In addition, the MIC/NKG2D interaction may lower the threshold of TCR activation by specific antigen and thus trigger or exacerbate an autoimmune response. Data from the literature strongly support the idea that the NKG2D-MIC activation pathway participates in the development of immune mediated disorders. Recently there had been some reports about a novel subset of NKG2D+ CD4+ T cells in some autoimmune disease such as rheumatoid arthritis, HTLV-1-associated neurologic disease, and Crohn’s diseases. Upregulation of MICA/B ligands and high level of IL-15/ TNF-αactivate the effector CD4+ T cells and induce the expression of NKG2D. This subset T cells show the deficiency of the surface marker of CD28 and can secret perforin and granzyme B acting as cytolytic and autoreactive T cells. Later, some groups have been reported that anomalous NKG2D expression on circulating CD4+ T cells in patients with Wegener's granulomatosis .
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the deposition of immune complexes with an inflammatory/necrotic phenomenon in different tissues, mainly kidney, skin, blood vessels and central nervous system. Multiple immune abnormalities are characteristic of this condition, including the synthesis of different autoantibodies, enhanced synthesis of IFN-γand defective immunoregulatory function. IFN-γis secreted by lymphoctyes in vivo and plays an essential role in immunologic defence even in immunoregulation. We and others previous study demonstrated that IFN-γparticipate in the crosstalk between NK cells and monocytes by inducing or enhancing the expression of MIC and mIL-15 on monocytes. Considering that IL-15 can induce NKG2D expression on CD4+ T cells, we wonder whether monocytes in patients with SLE aberrantly displayed enhanced expression of MIC and mIL-15 on the surface due to the increased concentration of serum IFN-γ. If this is true, we want to know whether there is a subpopulation of CD4+ T cells expressing NKG2D existing in SLE patients, which maybe induced by mIL-15 on CD14+ monocytes. It is of great interest to further dissect the mechanisms of NKG2D/MIC interaction during the crosstalk of CD4+ T cells and CD14+ monocytes.
Thus, in this study, we investigate the NKG2D receptor expression on CD4+ T cells as well as MIC and mIL-15 expression on CD14+ monocytes in SLE patients. The methods is as follows:1. We detected and analyze the frequency of CD4+NKG2D+ T cells and MIC+ monocytes and the expression of mIL-15 between SLE patients and normal control. Also, we analyzed whether there are correlation between the frequency of MIC+ monocytes and SLEDAI.2. We detected the concentration of IFN-γand IFN-αin sera of SLE patients and normal controls.Then we investigated the effects of IFN-γ, IFN-αon MIC expression of primary monocytes and monocytic cell lines, for example, THP-1 and U937. We also nalyzed whether there are correlation between the concentration of IFN-γin patients sera and MIC+ monocytes.3. With cocultue system, we investigated the effect of monocytes derived from SLE patients and normal controls on the induction of NKG2D receptor expression on CD4+ T cells. Furthermore, we decteted this effect of IFN-γ-treated monocytes on NKG2D expression in different time point and different cell ratio. In some expriments, anti-IL-15 antibodies were adding to the coculture system.4. We detected the activatory marker of CD25 and CD69 and IFN-γproduction of the cocultured CD4+ T cells. In some expriments, anti-IL-15 antibodies,anti-MICs antibodies and transwell were adding to the coculture system.5.We investigated the effect of IL-15 and NKG2D/MIC on the cocultured CD4+ T cells. We detected activatory marker of CD25 and CD69 , IFN-γlevel either using ELISA and intracellular cytokines staining , and the production of perforin and granzyme B in the absence or presence of transwell, anti-IL-15 Abs and anti-MIC Abs. In addition, we observed the proliferatin of cocultred CD4+ T cells by using Cell Counting Kit-8 ( CCK-8)
The results are as follows:1. In normal controls, the NKG2D expression was nearly not observed on CD4+ T PBLs (1.2-8.3%, mean 3.4±1.5%) compared with 8-33% (mean 20.1±7.3%) in SLE. The expression of MIC on monocytes is (5–12%, mean7.2±2.4%). In normal controls compared with (11–76%, mean 37±18.1%) in patients. When analyzing the expression of membrane bound IL-15 (mIL-15) on monocytes, we found that mIL-15 expression of CD14+ monocytes in SLE patients (25-48%, mean 36±7.3%) was significantly higher than those in normal controls (5-13%, mean 7.6±2. 5%) .The expression of MIC on monocytes is significantly correlated with SLEDAI. 2. Elevated serum IFN-γhas been found in SLE patients. Our results showed that the concentration of IFN-γin SLE patients (150.3-669.5 pg/mL, mean 429.7±145 pg/mL) was remarkablely higher than those in normal controls (18.8-88.2 pg/mL, mean 73.8±18.9pg/mL),while IFN-α(198.3-489.2pg/mL, mean319±86.1pg/mL) in patients compared with (58.8-322.2 pg/mL, mean151.9±78.5pg/mL) in normal controls. .The concentration of IFN-γin patients is significantly correlated with expression of MIC on monocytes. IFN-γcan upregulated the expression of MIC on primary monocytes and monocytic cell lines. 3. IFN-γpretreated monocytes or freshly isolated monocytes induced NKG2D expression on CD4+ T cells, and can activate CD4+ T Cells via NKG2D/MIC requiring IL-15. 4. Monocytes expressing MIC and mIL-15 promote NKG2D+CD4+ T cells activation via NKG2D/MIC interaction in a IFN-γ-dependent manner.5. The activated CD4+ T cells produced IFN-γand upregulated the MIC and mIL-15 on monocytes. Hence in a feedback , CD4+ T cells and monocytes can crosstalk in IFN-γand mIL-15 dependent manner via NKG2D/MIC interation and activate reciprocally. This crosstalk maybe contribute the exacerbation of the pathogenesis of SLE.
引文
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