转录因子Foxo4调节Th1细胞分化和功能的机制研究

Listeria monocytogenes (LM) are a kind of facultative intracellular bacteria, and it can lead serious infection of gastrointestinal and central nervous system. Based on previous studies, Th1 and IFN-γproduced by Th1 play an important role in adaptive immune response against LM infection. Foxo protein（Foxo1）plays a very important role in regulating T cells homeostasis and functions. However, it is still unknown that, how Foxo4, another member in Foxo family, functions in T cells development, differentiation and function. Our previous studies showed Foxo4 knock-down can enhanced Th1 differentiation and IFN-γproduction, and Foxo4 overexpression can get opposite results. Based on these, we are going to set up LM infection model on Foxo4 conditional knockout mice to test whether knocking out Foxo4 can enhance the adaptive immune response against LM infection, and investigate the relevant mechanism involved in that.

产单核细胞李斯特菌（LM）是一种兼性胞内寄生菌，能引起严重的胃肠道、全身性以及中枢神经系统的感染, 研究表明，LM感染早期的防御主要靠NK细胞分泌的IFNγ以及随之活化的巨噬细胞所介导的先天免疫，进入到获得性免疫阶段，则由Th1细胞以及分泌的IFN-γ起主要作用。Foxo蛋白（Foxo1）在维持T细胞稳态和功能方面发挥着重要的作用，然而作为Foxo家族的另一重要成员，Foxo4在调节CD4+ T细胞的分化、发育等方面的研究一直未见报道。通过前期的基因敲除和基因过表达的实验，我们发现Foxo4可以特异性地显著地影响Th1细胞的体外分化和其特异性细胞因子IFN-γ的产生。基于此，我们构建了Foxo4条件性基因敲除小鼠，并且计划用该小鼠建立LM感染模型以探讨Foxo4能否通过直接或间接靶向IFN-γ而参与控制抗LM感染相关的获得性免疫反应及其相关的分子机制。