Functional Implications of Tfh Cell Heterogeneity after Infection

摘要疫苗接种是历史上最重要的公共卫生成就之一。但我们 仍然不能诱导针对重要的人类病原体如流感的保护性免疫。因此，在本发明中， 传染病仍然是造成残疾和死亡的主要原因。一个“成功”的重要组成部分 疫苗是能够产生长寿命的浆细胞（LLPC）和记忆B细胞， 保护性抗体（Ab），并提供长期的预防性免疫。重要的是，LLPC的发展 记忆B细胞位于生发中心（GC）。因此，了解这些机制是至关重要的。 控制气相色谱反应。然而，尽管在该领域取得了重大进展，但我们对 控制GC反应的机制仍然有限。我们知识中的一个关键空白是“GC “命运决定”受到调节，特别是GC B细胞如何“选择”留在GC中分化 转化为高度突变的LLPC或成为记忆B细胞并离开GC。缺乏准确的知识， 微调GC输出的机制是设计新的 疫苗接种策略，以克服个别病原体的适应。在这方面，以前的研究表明， 肺中预先存在的流感特异性记忆B细胞在再感染后提供了关键的保护。 然而，控制肺记忆B细胞应答产生的因素仍然难以捉摸。我们认为 这些知识对于设计更有效的抗呼吸道病毒的疫苗接种策略是必不可少的， 例如流感或SARS-CoV 2。重要的是，CD 4+滤泡辅助性T细胞（Tfh）在免疫调节中起着重要作用。 促进GC B细胞应答。事实上，在缺乏Tfh细胞的情况下，GC反应和Ab介导的保护作用 都受损了因此，通常认为，接种疫苗后“增强的”Tfh细胞应答将导致免疫应答。 大大提高疫苗的效力。不幸的是，我们仍然不知道什么功能特性 定义“高质量”Tfh细胞应答。我们的初步数据表明，随着免疫反应的增强， 随着流感的进展，流感特异性Tfh细胞应答“进化”。因此，Tfh细胞的不同亚群 在感染流感后的不同时间出现。根据我们的数据，我们假设GC B细胞 与不同“风味”的Tfh细胞在感染后的不同时间相互作用， 信号，其暂时微调GC的输出和肺记忆B细胞的产生。的 本申请的长期目标是1）确定Tfh细胞的不同亚群在 控制存储器/LLPC微分平衡。2)来定义调节生成的机制 具有促进增强的B细胞介导的对呼吸道疾病的保护的能力的“高质量”Tfh细胞 病毒。3)为了确定分子和转录机制，控制的产生， 肺记忆B细胞和GC中记忆/LLPC分化平衡。我们相信这 知识对于设计针对呼吸道病毒的新疫苗接种战略至关重要。

SUMMARY. Vaccination is one of the most important public health achievements in history. However, we are still unable to induce protective immunity against important human pathogens, such as influenza. Thus, infectious diseases remain a major cause of disability and death. An essential component of a “successful” vaccine is the ability to generate long-lived plasma cells (LLPCs) AND memory B cells, which produce protective antibodies (Ab) and provide long-term prophylactic immunity. Importantly, the development of LLPCs and memory B cells occurs in the germinal center (GC). Thus, it is essential to understand the mechanisms that control the GC reaction. However, despite significant advances in the field, our understanding of the mechanisms that control the GC responses is still limited. One of the critical gaps in our knowledge is how “GC fate decisions” are regulated, particularly how GC B cells “choose” between staying in the GC to differentiate into highly mutated LLPCs or becoming memory B cells and leave the GCs. The lack of precise knowledge of the mechanisms that fine-tune the output of the GC is one of the main limitations when designing new vaccination strategies to overcome individual pathogen adaptions. In this regard, previous studies demonstrate that preexisting influenza-specific memory B cells in the lungs provide critical protection after reinfection. However, the factors that control the generation of lung memory B cell responses remain elusive. We believe this knowledge will be essential for designing more efficient vaccination strategies against respiratory viruses, such as influenza or SARS-CoV2. Importantly, CD4+ T follicular helper (Tfh) cells play a fundamental role in promoting GC B cell responses. In fact, in the absence of Tfh cells, GC responses and Ab-mediated protection are impaired. Thus, it is generally believed that an “enhanced” Tfh cell response after vaccination will significantly improve the efficacy of vaccines. Unfortunately, we still do not know what functional properties define a “high-quality” Tfh cell response. Our preliminary data demonstrate that, as the immune response progresses, the influenza-specific Tfh cell response “evolves.” As a consequence, different subsets of Tfh cells are present at different times after influenza infection. Based on our data, we hypothesize that GC B cells interacting with different “flavors” of Tfh cells at different times after infection receive qualitatively different signals, which temporarily fine-tunes the output of the GC and the generation of lung memory B cells. The long-term goals of this application are 1) To determine the role played by distinct subsets of Tfh cells in controlling the memory/LLPC differentiation balance. 2) To define the mechanisms that regulate the generation of “high quality” Tfh cells with the ability to promote enhanced B cell-mediated protection against respiratory viruses. 3) To determine the molecular and transcriptional mechanisms that control the generation of pulmonary memory B cells and the memory/LLPC differentiation balance in the GCs. We believe this knowledge will be essential for designing new vaccination strategies tailored against respiratory viruses.