TCF-1在Tem/Tcm转变中的作用及调节机制研究

Memory T cell is the main principle of the function of vaccine, of them,Tcm is the important subgroup, But the current Tem/Tcm transition is still controversial, the molecular mechanism is not clear and specific.Previous studies have confirmed that TCF-1 plays a decisive role in the formation and maintenance of memory T cells.And further found that TCF-1 deleted memory T cells only showed the phenotype of Tem.Therefore, we speculate that TCF-1 plays an important role in the transformation of Tem/Tcm.This project intends to establish ERT2Cre induced TCF-1 knockout and TCF-1 induced Tet-ON high expression mouse model,In vivo lymphocyte choroid plexus meningitis virus infection,the use of "loss- and gain-of-function" strategy research confirmed that TCF-1 plays an important role in the transformation of Tem/Tcm,in order to provide new hypotheses and new evidence for the controversy about the fate of Tem/Tcm cells in the world;Furthermore,through Microarray and ChIP-Seq looking for target genes and verification, to clarify the molecular mechanism of TCF-1 regulation, in order to provide molecular mechanisms and evidence for the design, optimization, and use of vaccines and adjuvant for vaccine design.

记忆T细胞是疫苗发挥功能的主要原理，其中Tcm是其重要的亚群，但是目前Tem/Tcm转变尚存争议，且具体的分子机制不清楚。前期研究已证实TCF-1对记忆T细胞的形成和维持具有决定性的作用，而且进一步研究发现TCF-1缺失的记忆T细胞只表现出Tem的表型，因此，我们推测：TCF-1在Tem/Tcm分化及维持中具有重要的作用。本项目拟建立ERT2Cre诱导TCF-1敲除以及Tet-ON诱导TCF-1高表达小鼠模型，通过体内淋巴细胞脉络丛脑膜炎病毒感染，利用“loss- and gain-of-function”研究策略证实TCF-1在Tem/Tcm转变中的关键作用，为国际上关于Tem/Tcm转变的争议提供新假说和新证据；通过Microarray及ChIP-Seq寻找靶基因并进行验证，阐明TCF-1调控的分子机制，为疫苗的设计，疫苗和佐剂使用的优化，提供分子机制和依据

在急性病毒感染模型中，转录因子BCL6可以与Tcf7基因调控区直接结合从而促进效应性CD8+T细胞的扩增和MPEC细胞的形成。相反，在记忆性CD8+T细胞中，BCL6不能促进TCF-1的表达，从而也不能促进其稳态维持