鞭毛素蛋白的胞内受体NLRC4对抗原特异性CD8应答的抑制作用研究

Flagellin is a type of pathogen-associated molecular patterns (PAMPs) shared by a series of bacterials. It could be recognized by two different signal pathways of innate immune response, including TLR5 and NLRC4 pathways, and thus it is involved in both extracellular and intracellular stages of immune recognization. Besides the direct removal of intracellular pathogens, activation of NLRC4 results in production of active IL-1β and IL-18, which are considered to modulate the adaptive immune response, and thus play a role in the long-term protection for infection. Sauer J. found a potential relationship between NLRC4 pathway and impairment of CD8 response in bacterial infection model. Our previous results indicate that flagellin was able to activate NLRC4 in multiple antigen presenting cells derived from different organs, and produced IL-1β. According to our data, we presume that flagellin activated NLRC4 pathway of the APCs may result in a Th2 bias and impairment of CD8 response. This proposal will focus on the modulation of antigen-specific response by NLRC4 activated DCs, especially the specific CD8 cells. Moreover, we will compare two classes of specific CD8 cells, to investigate whether there is a diverged regulation for flagellin-specific and exogenous protein-specific CD8 cells. Thus, our proposal will provide the experimental foundations to extended study the immune regulatory function of flagellin, and its role in the long-term immonological protection for infection.

Flagellin是一种细菌的病原相关分子模式，能够激活天然免疫的TLR5和NLRC4通路，分别在胞外和胞内水平进行免疫识别。激活NLRC4通路除了直接清除胞内致病菌，其效应分子IL-1β、IL-18等能够调节获得性免疫应答，影响其对机体的长期保护。在细菌感染模型的研究中发现，NLRC4通路与CD8应答水平降低有关。我们的前期结果显示，在多种不同部位的APC细胞中，flagellin均能有效地活化NLRC4通路并产生IL-1β；据此推测，flagellin作用于APC细胞的NLRC4通路，促进Th2应答倾向，抑制CD8细胞应答。本项目旨在研究DC细胞内NLRC4受体的激活对特异性应答，尤其是CD8应答的影响，探讨NLRC4对于抗flagellin和外源抗原的两种不同特异性CD8细胞的调节作用的异同，为深入研究flagellin的免疫调节功能，及其在机体的长期保护性免疫中的作用提供依据。

Flagellin是一种细菌的病原相关分子模式，能够激活天然免疫的TLR5和NLRC4通路。激活NLRC4产生效应分子IL-1β、IL-18等，并导致细胞发生“炎症性死亡”，从而对特异性免疫应答进行调节。本项目旨在研究NLRC4激活所产生的特异性免疫应答的特征，阐明其发挥免疫调节作用的机制，比较其对于抗flagellin自身和抗外源抗原的特异性免疫应答的异同。在本研究中，我们利用一系列不同功能活性的重组沙门氏菌来源的flagellin（FliC）免疫动物，分析其诱导产生的特异性免疫应答水平。结果表明，NLRC4缺失的FliC诱导所产生的抗- FliC特异性抗体滴度明显高于野生型FliC，NLRC4呈现出对特异性免疫应答的抑制作用。这种抑制作用与DC细胞无关，而可能与NLRC4诱导的巨噬细胞减少效应有关。将小鼠体内的巨噬细胞清除后，能够消除NLRC4引起的抑制，NLRC4突变的FliC和野生型FliC诱导同样水平的免疫应答。此外，利用FliC-HBc融合蛋白免疫小鼠后发现，NLRC4的激活不仅能够抑制FliC特异性免疫应答，还能够对外源蛋白HBc的免疫应答产生抑制。我们的结果表明，NLRC4的激活能够通过下调体内巨噬细胞的数量，从而抑制TLR5介导的免疫增强效应。

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