急性病毒感染中转录因子Tbet对TFH应答的调控及机制研究

TFH是辅助B细胞进行体液免疫应答的关键细胞亚群，理解不同微环境下的TFH分化对提高其辅助B细胞产生抗体的能力至关重要。急性病毒感染同时诱导病毒特异性的TH1及TFH应答，而T-bet通常被认为是促进TH1细胞，而抑制TFH细胞分化的关键转录因子。但是，我们前期发现，在急性病毒感染下，病毒特异性TFH细胞上调T-bet, 将其条件性敲除并不能使TFH细胞数量增多，相反抑制了TFH应答，提示：T-bet在急性病毒感染下可能正向调控TFH应答。验证此假说，本研究拟采用LCMV急性病毒感染模型及系列条件性敲除小鼠，研究不同时空条件下T-bet对TFH细胞的调控方式及其分子机制。明确急性病毒感染下T-bet调控TFH细胞的分子机理将加深我们对体液免疫应答的理解，为抗病毒疫苗设计提供理论基础。

Follicular helper T (TFH) cells are a CD4+ helper subset specialized in the provision of help to B cells in humoral immunity. Understanding the differentiation of these important cells in different microenvironment will facilitate its ability in helping B cell to secret antibody. Following acute viral infections, antigen-specific naive CD4 T cells predominantly differentiate into TH1 and TFH cells. Despite generally being considered an enhancer of TH1 differentiation, and an inhibitor of TFH differentiation, T-bet conditional depletion did not increase the number of TFH cells; in contrast, TFH response was deeply repressed in T-bet-/- CD4 T cell, suggesting T-bet positively regulate TFH response during acute viral infection. To confirm this, this project will use LCMV acute viral infection model, combine with series conditional knockout mice, to explore the regulatory function of T-bet in different stages of formation and differentiation of TFH cells. The achievements will help for better understanding of humoral immunity and provide fundamental basis for high-efficiency vaccine development.