滤泡辅助性T细胞调节新冠病毒特异性抗体产生及型别转换的作用研究

病毒特异性抗体在抗新型冠状病毒免疫中发挥重要作用。病毒特异性抗体的产生及型别转换依赖于滤泡辅助性T细胞。在SARS-CoV-2感染中，滤泡辅助性T细胞的分化和功能及其对抗体产生和型别转换的作用仍不明确。前期临床研究发现，不同型别病毒特异性抗体的动态特征与新冠病毒感染的疾病进展密切相关。我们提出SARS-CoV-2病毒感染导致Tfh异常分化，调控B细胞反应及抗体产生和型别转换，影响疾病的发生。本项目通过建立SARS-CoV-2病毒感染小鼠模型，借助单细胞转录组和免疫组库测序、多色流式、免疫荧光等方法，阐明SARS-CoV-2感染中Tfh细胞的分化特征及其与B细胞分化及抗体产生和型别转换的关系，并借助Bcl6条件性敲除小鼠感染模型和体外共培养实验分析不同亚群Tfh对B细胞及抗体产生的调控作用。本项目的开展有助于揭示新冠病毒感染中Tfh对不同型别抗体产生的作用，为机体免疫平衡的调控提供参考。

Viral-specific antibodies are essential for immune protection or immunopathogenesis during SARS-CoV-2 infection. B cell response and antibody production are regulated by follicular helper T cells(Tfh). However, it remains unclear whether the differentiation of Tfh subsets contributes to the balance of antibody production and isotype switch. Clinical data has shown that dynamics of antibody isotypes correlated with disease severity of COVID-19 patients. Therefore, we hypothesize that the dysregulation of Tfh differentiation during SARS-CoV-2 infection resulted in the imbalance of antibody production and isotype switch. In this project, we will establish ACE2 humanized mice and SARS-CoV-2 infection model by intranasal inoculation with different doses of virus. Flow cytometry, immune fluorescence staining, and single-cell RNA sequencing and immune profiling will be used to characterize the Tfh and B cells. Bcl-6 conditional knockout mice infection model and in vitro co-culture experiment also be used to validate the regulation of Tfh subsets on B cells and antibody production. This study will provide new insights into the regulation of antibody response and the immunopathogenesis of COVID-19.