凋亡信号和免疫微环境对树突状细胞的免疫调控作用

发布时间：2018-08-30 14:08

【摘要】：免疫自稳是免疫应答的最重要的特征之一,它保证了免疫应答的自限性,即当外来病原体或者抗原被机体清除后,免疫应答会逐渐减弱直至恢复至免疫系统的静息状态,以维持机体的相对的平衡,这提示机体必然存在相应的正负反馈调节机制来实现这一功能。在免疫应答过程中,抗原递呈细胞发挥着桥梁的作用,连接着外来的抗原的识别和相应的效应细胞的应答。而树突状细胞(Dendritic cells,DC)是目前已知的功能最强的专职抗原递呈细胞,具有直接刺激初始T细胞增殖的独特功能。它们主要以非成熟状态存在于非淋巴组织内,此时,获取抗原是其主要功能。当外界的病原微生物或其它异物侵入机体,DC获取抗原,迁移至外周免疫器官中,在此过程中,DC获得成熟,主要表现为抗原摄取能力降低,而抗原递呈功能增强。在外周免疫器官中,DC将抗原递呈给T细胞,从而激发免疫应答。根据机体的免疫自稳的原则,DC不可能持续地活化T细胞,那么,完成了抗原递呈功能的DC,其最终命运是怎样的呢?目前的研究表明,DC在活化T细胞的同时,亦受到来自于T细胞的作用,引起自身的凋亡,以有效地下调免疫应答。目前普遍认为,成熟DC在完成抗原提呈功能而激活T细胞之后,通过自身发生凋亡而实现免疫负向调控。但是,由于免疫应答都是在外周免疫器官的微环境中进行的,而免疫微环境由基质细胞和细胞外基质组成,含有众多的膜分子和可溶性的细胞因子,因此,外周免疫器官特殊的微环境在为免疫应答的进行提供良好条件的同时,也必将对参与免疫应答的细胞的功能状态和命运有所调节。因此,脱离基质微环境的影响而研究和谈论免疫细胞在应答后的命运归宿,所得到的结论不可能反映在体的真实情况。有实验证实,在不需要外来细胞因子的作用下,脾脏基质长期培养体系(LTC)中,可诱导造血前体细胞产生DC样细胞,具有DC的形态和功能。也有研究发现,肺部、脑组织和肾脏内的DC在微环境的作用下,其功能发生变化,成为具有调节性作用的DC,我们以前的实验也证明,用来源于脾脏的内皮型基质细胞ESSC来模拟免疫微环境,将成熟DC与其共培养后,成熟DC获得了继续增殖的能力,而且,其功能也发生了质的变化,由原来的刺激T细胞增殖变成只能诱导T细胞活化而不能刺激其增殖,而且可以抑制成熟DC诱导的T细胞的增殖。这提示免疫微环境对于DC的分化发育和功能具有很强的调节功能。细胞凋亡是细胞维持机体内环境稳定的机制之一,一旦细胞凋亡发生异常,机体将发生肿瘤、自身免疫性疾病等等。也有实验证明,不同器官的微环境或者通过基质细胞表面的分子或者通过分泌的可溶性因子,有助于不同类型的细胞免于凋亡(其实,实验中仅仅是观察对于细胞凋亡的预防作用)。比如,胸腺的上皮细胞可以抑制皮质激索引起的胸腺细胞
[Abstract]:Immune self-stabilization is one of the most important characteristics of immune response, which ensures the self-limitation of immune response, that is, when foreign pathogens or antigens are removed by the body, the immune response will gradually weaken until the resting state of the immune system, in order to maintain the relative balance of the body, suggesting that the body must have corresponding positive and negative feedback regulation. Node mechanism to achieve this function.
In the process of immune response, antigen presenting cells act as a bridge between the recognition of foreign antigens and the response of corresponding effector cells. Immature state exists in non-lymphoid tissues, at this time, antigen acquisition is its main function. When external pathogenic microorganisms or other foreign bodies invade the body, DC acquires antigens and migrates to peripheral immune organs. During this process, DC matures, mainly manifested by decreased antigen uptake and enhanced antigen presenting function. According to the principle of immune self-stabilization, DC can not activate T cells continuously. What is the ultimate fate of DC which has completed the function of antigen presenting? Current studies have shown that DC is activated by T cells as well as T cells, causing itself. At present, it is generally believed that mature DCs activate T cells after completing antigen presenting function and achieve negative immune regulation through their own apoptosis.
However, because the immune response is carried out in the microenvironment of the peripheral immune organs, and the immune microenvironment is composed of stromal cells and extracellular matrix, containing a large number of membrane molecules and soluble cytokines, the special microenvironment of the peripheral immune organs will provide good conditions for the development of the immune response at the same time. The functional status and fate of the cells involved in the immune response are regulated. Therefore, the fate of the immune cells after the response can not be reflected in the conclusions drawn from the study and discussion of the fate of the immune cells without the influence of matrix microenvironment. Experiments have confirmed that the splenic matrix is cultured for a long time without the use of foreign cytokines. In LTC system, DC-like cells can be induced from hematopoietic progenitor cells, which have the morphology and function of DC. It has also been found that the function of DC in lung, brain and kidney changes under the action of microenvironment and becomes a DC with regulatory effect. Our previous experiments have also proved that ESSC, an endothelial stromal cell derived from the spleen, can be used as a DC. After co-culture with mature DCs in simulated immune microenvironment, mature DCs acquired the ability to continue to proliferate, and their functions changed from stimulating T cell proliferation to inducing T cell activation but not proliferation, and inhibiting T cell proliferation induced by mature DCs. It has a strong regulatory function in differentiation, development and function of DC.
Cell apoptosis is one of the mechanisms by which cells maintain homeostasis. Once abnormal apoptosis occurs, the body will develop tumors, autoimmune diseases and so on. For example, thymic epithelial cells inhibit cortex-activated index thymocytes
【学位授予单位】：第二军医大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R392

【共引文献】