小鼠树突状细胞上4-1BB分子的功能研究
发布时间：2019-03-09 17:32
【摘要】： 树突状细胞(DCs)是体内功能最强的专职抗原递呈细胞(APC),能摄取并加工处理免疫原性多肽,以MHC分子-抗原肽复合物形式表达于细胞表面,MHC分子/抗原肽复合物能被抗原特异性T细胞受体(TCR)识别,联合DCs表面的共刺激分子,为T细胞相关免疫反应提供了启动信号,进而通过辅助型T细胞调节B细胞增值,在免疫应答和免疫耐受的诱导中具有独特的地位,是介导先天性免疫和获得性免疫的桥梁。 DCs以未成熟状态广泛分布于人体各器官,在摄取抗原或接受到炎症因子如LPS、IL-1、TNF-α、CD40配体刺激后,DCs吞噬能力下降,表面黏附分子表达发生改变,CD80、CD86、MHCⅡ等表面分子表达升高,进入成熟状态,转移到淋巴结T细胞区域,刺激T细胞分化增殖,从而启动免疫应答。 4-1BB分子(CD137)为Ⅰ型糖蛋白,是肿瘤坏死因子(TNF)受体超家族的重要成员。4-1BB分子首先发现于小鼠活化T细胞表面,在NK细胞、NKT细胞、CD4~+CD25~+调节性T细胞和骨髓来源的单核、多个核细胞上都有表达,该分子提供的共刺激信号能有效促进CD4~+、CD8~+T细胞增殖以及细胞因子分泌,维持T细胞较长时间克隆扩增并拮抗活化诱导凋亡(AICD)。最近有研究表明,DCs也可组成型表达4-1BB分子,并且该分子介导的信号能促进DCs表型的改变以及功能的成熟。 本研究使用4-1BB激发型抗体2A激发经过磁珠纯化的小鼠骨髓来源树突状细胞(BMDC)表面4-1BB分子,以揭示DCs表面4-1BB分子的功能。 本文第一部分研究了4-1BB分子激发对肿瘤上清诱导的DCs凋亡的拮抗作用。研究结果表明,通过4-1BB激发型抗体2A激发DCs上4-1BB信号可以有效对抗小鼠黑色素瘤B16上清所诱导的DCs凋亡,和CD40激发型抗体1c10所介导的CD40信号效果类似但较弱。进一步研究发现,激发4-1BB信号可以诱导DCs胞内NF-κB p65亚基从胞浆向核内转移,表明DCs上4-1BB信号可能通过包含NF-κB在内的胞内信号传导途径达到抗凋亡功能。 第二部分研究了经过4-1BB激发成熟的DCs对T细胞的影响。检测表明,淋巴细胞混合培养3～5天后,CD40和4-1BB信号刺激后DCs组均可在显微镜下观察到CD4~+T细胞的增殖。在培养第5天,我们检测到CD40和4-1BB信号刺激后DCs可使部分CD4~+T表面出现Th1细胞标志性分子Tim3的表达。这说明经过4-1BB信号刺激分化成熟的DCs能有效刺激CD4~+T细胞向Th1细胞分化增殖。但在增殖的同时,和CD40信号组不同,我们观察到4-1BB信号组出现强烈T细胞凋亡,并且凋亡率随着时间的增加而增长。 本研究表明,DCs上4-1BB信号的激活能通过包含NF-κB通路在内的胞内信号传导途径向DCs传递一个免疫信号,增强DCs对抗肿瘤上清诱导凋亡的能力,并能通过激活DCs,刺激部分CD4~+T细胞向Th1细胞分化增殖。但同时,4-1BB信号活化的DCs可能通过某种途径诱导活化的CD4~+T细胞凋亡。这些研究结果将为4-1BB激发型抗体的肿瘤免疫治疗和自体性免疫疾病治疗提供重要参考。
[Abstract]:Dendritic cells (DCs) are the most potent antigen presenting cells in vivo. (APC), can absorb and process immunogenic peptides and express them in the form of MHC molecule-peptide complexes. MHC / peptide complexes can be recognized by antigen-specific T cell receptor (TCR), combined with costimulatory molecules on the surface of DCs, which provide a start-up signal for T-cell-related immune response, and then regulate B cell proliferation through helper T cells. It plays a unique role in the induction of immune response and tolerance, and is the bridge between innate immunity and acquired immunity. DCs is widely distributed in various organs of human body in immature state. After ingesting antigen or receiving stimulation of inflammatory factors such as LPS,IL-1,TNF- 伪 and CD40 ligand, the phagocytosis of DCs decreases, the expression of surface adhesion molecules changes, and CD80,CD86, occurs. The expression of surface molecules such as MHC 鈪，
本文编号：2437700
[Abstract]:Dendritic cells (DCs) are the most potent antigen presenting cells in vivo. (APC), can absorb and process immunogenic peptides and express them in the form of MHC molecule-peptide complexes. MHC / peptide complexes can be recognized by antigen-specific T cell receptor (TCR), combined with costimulatory molecules on the surface of DCs, which provide a start-up signal for T-cell-related immune response, and then regulate B cell proliferation through helper T cells. It plays a unique role in the induction of immune response and tolerance, and is the bridge between innate immunity and acquired immunity. DCs is widely distributed in various organs of human body in immature state. After ingesting antigen or receiving stimulation of inflammatory factors such as LPS,IL-1,TNF- 伪 and CD40 ligand, the phagocytosis of DCs decreases, the expression of surface adhesion molecules changes, and CD80,CD86, occurs. The expression of surface molecules such as MHC 鈪，
本文编号：2437700
本文链接：https://www.wllwen.com/yixuelunwen/shiyanyixue/2437700.html
最近更新
教材专著
