细胞凋亡、坏死样凋亡、焦亡对机体获得性免疫调控作用的比较研究

Apoptosis, necroptosis and pyroptosis are different types of programmed cell death and participate in innate immunity. The death of infected cells leads to the loss of pathogen replicating niche, and the secretion or release of intracellular substances during these processes also regulate adaptive immunity. Different intracellular substances secreted or released by apoptotic, necroptotic and pyroptotic cells could stimulate different immune responses. To promote their infection, pathogens have been evolved to suppress certain type of cell death. On the other hand, the parallel existence of various cell death pathways and the substitution among them in host organisms do protect the host from infection efficiently. Since different cell death types coexist in many pathological processes, it is difficult to study the specific function of each death type, but the specific function of each cell death type is the foundation for the understanding of the role of cell death in vitro and in vivo. Chemically-induced oligomerization of the core protein of apoptotic, necroptotic and pyroptotic pathways could specifically result in cell death of corresponding types, which allows us to study the specific effect of these three types of cell death. Based on this promising system, we would comprehensively investigate the role of apoptotic, necroptotic and pyroptotic cells to adaptive immune response processes, such as dendritic cell maturation, antigen presentation, T cell proliferation and activation, neutralizing antibody production, and their effects on the pathological process of pathogen infection.

凋亡、坏死样凋亡和焦亡是不同的程序性细胞死亡方式，是天然免疫抵抗病原体侵染的重要机制。被感染细胞通过凋亡/坏死样凋亡/焦亡使病原体失去复制场所，并分泌或释放细胞内容物调控获得性免疫。三种死亡方式分泌/释放物的不同会导致不同的免疫响应。病原体通过多种策略抑制宿主细胞死亡以促进感染，机体则通过多种细胞死亡方式并存及不同细胞死亡方式间相互替代来实现对病原体的有效防御，因而机体病理过程中往往都是几种死亡方式的混合，很难清晰地阐述某一细胞死亡方式的具体生物学效应。人为地使凋亡、坏死样凋亡和焦亡过程中的核心功能蛋白多聚化可在体内外特异性诱导细胞凋亡、坏死样凋亡和焦亡，为研究这三种细胞死亡的具体生物学功能提供了研究系统。本项目以此系统为基础，深入研究凋亡/坏死样凋亡/焦亡细胞对获得性免疫中树突状细胞成熟分化，抗原递呈，T细胞增殖活化及中和抗体产生等过程的调控作用以及对病原体感染的病理进程的影响。

程序性细胞死亡在响应病毒感染，限制癌细胞生长和调节器官稳态等生命活动中具有重要的功能。程序性细胞死亡主要分为细胞凋亡，细胞坏死样凋亡和细胞焦亡。这三种细胞死亡形式的调控机制、执行方式和导致的后果各不相同。细胞通过激活Caspase级联反应，诱导细胞膜保持完整的细胞凋亡。而细胞坏死样凋亡和细胞焦亡则是一种细胞膜裂解性死亡形式，会导致众多细胞内容物质释放，促进免疫炎症发生。本项目旨在比较三种不同死亡方式对于获得性免疫调控的作用，首先我们成功建立了特定诱导单纯的细胞凋亡、细胞坏死样凋亡和细胞焦亡的研究模型，并发现坏死样凋亡细胞而非凋亡的细胞能够释放出大量损伤相关分子模式（Damage- Associated Molecular Patterns ，DAMPs），且更能促进树突状细胞的成熟；发现发生坏死样凋亡的细胞能显著诱导出CD8+ T 细胞的交叉致敏，且此过程NF-κB的活化不是必需的。在此基础上，本项目进一步研究了三种死亡方式对于肿瘤微环境免疫细胞招募的影响，发现通过特定效应分子多聚化诱导的三种死亡细胞能招募不同的肿瘤浸润淋巴细胞；发现细胞坏死样凋亡具有更强的免疫原性，暗示其可能是一个可行的肿瘤疫苗产生手段；发现专职性吞噬细胞和非专职吞噬细胞对于坏死样凋亡和焦亡细胞的吞噬效率明显高于对凋亡细胞的吞噬效率。最后，利用病原体感染模型，我们发现不同的细胞死亡通路存在着广泛的互相影响，共同影响宿主对于病原体的免疫应答反应和相关病理进程。