ICOS、4-1BB通过Survivin维持T细胞分裂及存活的研究

发布时间：2018-07-15 09:50

【摘要】：T 细胞发挥功能时间的长短在一定程度上显示了机体免疫力及保护性的强度。T细胞活化至少需要两种信号,第一信号主要来自T 细胞受体(TCR)与MHC 分子-抗原肽复合物的特异性结合,此信号诱导细胞表面高亲和力IL-2R 的表达及细胞增殖;其二是T 细胞共刺激受体与抗原递呈细胞(APCs)上的配体相互作用,此信号对于增强细胞因子的产生,延长T 细胞存活的时间都是必需的。 CD28/CTLA-4-B7.1/B7.2是最早深入研究的共刺激途径之一,来自该途径的共刺激信号协助TCR启动细胞周期进程,对细胞的活化和耐受发挥着重要调节作用。但众多证据表明CD28并不是唯一的共刺激分子[3-6],也有研究表明,T细胞免疫应答(Immune Response,IR)后期,来自CD28的共刺激信号对活化后的T细胞发挥效应并非必不可少,甚至不能称为主要的信号[7-9];IR后期,T细胞活化后表达的ICOS、OX40、4-1BB对维持T细胞存活,促进T细胞功能方面发挥主要作用。本研究中,我们关注的是免疫应答后期T细胞生物学效应的维持,在CD28、CD40L的协助下经第一信号启动增殖后,T细胞还需要进一步分裂,增强效应T细胞的克隆扩增;另外,还需要抑制活化后凋亡以便维持功能,ICOS、OX40、4-1BB是此期间内发挥功能的主要分子,确认经它们调控的、维持T细胞分裂及存活的下游分子,对于阐明共刺激分子信号传导及临床应用具有重要意义。Survivin是一个分子量约16Kda的凋亡抑制蛋白(IAP)[11],需要在P34cdc2激酶作用下,磷酸化第34位的苏氨酸(Thr34)才能发挥作用[12],Survivin Thr34突变体或反义Survivin可以抑制Survivin的作用。T细胞活化后,可以检测到Survivin的表达,其表达水平在培养的2～4天达到高峰,第6天下降,Survivin在活化的T细胞中表达的时相特点同OX40、4-1BB、ICOS等共刺激分子相似,提示Survivin与这些分子在功能上存在关联。Survivin是迄今发现的最强的凋亡抑制因子,另外它在细胞周期中也有明确的作用,其表达可以激活细胞周期激酶CDK2-cyclinE,使转录复合物Rb磷酸化,从而细胞由G1期迅速进入S期。综上分析,Survivin的表达特点及其抑制细胞凋亡和调节细胞分裂的双重功能提示OX40、4-1BB、ICOS等迟相作用共刺激分子很可能通过Survivin维持IR晚期T细胞分裂及存活。已有研究表明,OX40 共刺激信号可通过上调Survivin 的表达来调控T 细胞的寿命,ICOS、4-1BB 的生物学特点与OX40 极为相似,都是活化诱导表达并在IR 晚期发挥功能,那么ICOS 与4-1BB 是否同样通过Survivin 来调节T 细胞活化和存活呢?
[Abstract]:The duration of T cell function to some extent indicates that at least two signals are needed for immune and protective intensity of T cell activation. The first signal mainly comes from the specific binding of T cell receptor (TCR) with MHC molecule antigen peptide complex. This signal induces the expression of high affinity IL-2R and cell proliferation on the cell surface. The other is the interaction between T cell costimulatory receptor and ligand on antigen-presenting cells (APCs), which enhances cytokine production. It is necessary to prolong the survival time of T cells. CD28 / CTLA-4-B7.1 / B7.2 is one of the earliest costimulatory pathways studied in depth, and costimulatory signals from this pathway assist TCR to initiate cell cycle progression. It plays an important role in regulating cell activation and tolerance. But there is plenty of evidence that CD28 is not the only costimulatory molecule [3-6], and studies have shown that in the late stages of the immune response (Immune response IR), costimulatory signals from CD28 are not essential for activated T cells. ICOS OX404-1BB, which is not even a major signal [7-9], plays a major role in maintaining T cell survival and promoting T cell function. In this study, we focus on the maintenance of biological effects of T cells in the late stage of immune response. The T cells need to further divide and enhance the cloning and amplification of effector T cells after the proliferation of T cells is initiated by the first signal with the help of CD28 and CD40L. It is also necessary to inhibit activated apoptosis in order to maintain function. ICOS OX40X404-1BB is the major molecule that functions during this period, and recognizes the downstream molecules that are regulated by them to maintain T cell division and survival, Survivin is an inhibitor of apoptosis protein (IAP) with molecular weight of about 16Kda [11], which needs to be acted on by P34cdc2 kinase. Thr34 (phosphorylated) can play a role [12] survivin Thr34 mutant or antisense survivin can inhibit the activation of survivin. After activation of T cells, survivin expression can be detected. The expression level of survivin reached its peak at 24 days after culture. On the 6th day, the expression of survivin in activated T cells was similar to that of costimulatory molecules such as OX404-1BBICOS, suggesting that survivin is the strongest inhibitor of apoptosis. The expression of CDK2-cyclin E activates CDK2-cyclin E and phosphorylates the transcription complex RB, which leads to the rapid entry of cells from G1 phase into S phase. The features of survivin expression and its dual functions of inhibiting apoptosis and regulating cell division suggest that the delayed costimulatory molecules, such as OX404-1BBN ICOS, may maintain T cell division and survival in late IR stage by survivin. It has been shown that OX40 costimulatory signal can regulate the survival of T cells by up-regulating the expression of survivin. The biological characteristics of ICOS4-1BB are very similar to those of OX40. They are activation-induced expression and function in the late stage of IR. So does ICOS and 4-1BB regulate T cell activation and survival through survivin?
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：R392

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