B细胞启动抗病毒样颗粒CD4+ T细胞反应机制的研究

The initiation of the adaptive T cell response depends on the presentation of foreign antigen by cells expressing MHC II and the stimulatory signals from innate immune receptors. It is widely accepted that dendritic cells (DC) are the most important antigen-presenting cells （APC） for the activation of CD4+ T cells. Although B cells express MHC II, and their role of antigen-presentation has been implicated in the pathogenesis of many autoimmune diseases, it is commonly accepted that B cells cannot normally activate naïve CD4+ T cells. Recently, we discovered that when immunized with a bacteria phage derived virus-like particle (VLP), the activation of CD4+ T cells are highly dependent on the presence of antigen-specific B cells. Moreover, the intrinsic TLR signaling of B cells can strongly promote the differentiation of Tfh and Th1 cells. The understand the underlying mechanisms, we are going to examine how B cells capture and present VLP antigen to CD4+ T cells, and how their TLR signaling promote T cell differentiation. Our study will not only shed light on the role of B cell antigen-presentation in infection and in autoimmune diseases, but will also provide novel tools and rules for developing vaccines and immune therapy.

T细胞免疫反应的启动依赖于外源性抗原和天然免疫信号的共同刺激。传统观点认为树突状细胞（DC）是活化CD4+ T细胞反应最重要的抗原呈递细胞（APC）。虽然B细胞表达MHC II，并且其抗原呈递功能也被发现与多种自身免疫性疾病的发病过程密切相关，但是目前普遍认为B细胞并不参与初始CD4+ T细胞的活化。最近，我们发现用一种噬菌体来源的病毒样颗粒（VLP）抗原免疫后，CD4+ T细胞的活化高度依赖抗原特异性的B细胞；并且B细胞的TLR免疫信号能强烈地促进CD4+ T细胞的分化成滤泡辅助T细胞（Tfh）和Th1细胞。针对这个现象，我们拟于对B细胞捕获和呈递 VLP抗原、促进CD4 T细胞分化的机制进行研究。我们的研究不但将为B细胞抗原呈递功能在感染和自身免疫疾病中发挥作用的机制提供线索，还将为发展新型疫苗和免疫治疗提供工具和理论依据。

CD4+ T细胞免疫反应的启动依赖于抗原提呈细胞（APC）通过MHCII提供的抗原和天然免疫信号的共同刺激。传统观点认为树突状细胞（DC）是活化CD4+ T细胞反应最重要的APC。虽然B细胞表达MHCII，并且其抗原呈递功能与多种自身免疫性疾病的发病过程密切相关，但是目前普遍观念认为B细胞并不参与初始CD4+ T细胞的活化。我们发现一种病毒样颗粒（VLP）抗原Qb-VLP能被抗原特异性B细胞捕获和提呈，并启动初始CD4 T细胞的活化。本项目研究中，我们利用在B细胞或者DC上特异性敲除TLR信号的小鼠，发现Qb-VLP诱导Tfh和Th1分化依赖B细胞TLR信号，而非DC TLR信号；利用BCR转基因小鼠，我们阐明了Qb-VLP可以通过抗原特异性的B细胞活化初始CD4+ T细胞；最后，我们还利用DC诱导删除小鼠模型，证实Qb-VLP活化CD4+ T细胞可以完全不依赖DC，其活化的CD4+ T细胞可以支持生发中心（GC）反应发生。在此基础上，我们提出了靶向B细胞TLR信号的病原样抗原（PLA）疫苗策略。在新冠疫情爆发后，我们还发展出了针对新冠病毒的PLA疫苗，并在非人灵长类动物研究中证实PLA疫苗能够提供有效的免疫保护作用。