Innate Regulation of Adaptive Immunity

描述（由申请人提供）：生产能够中和目标病原体的强效高亲和力抗体仍然是疫苗研究的中心目标。虽然我们对抗体分子本身了解得很多，但对产生抗体的高亲和力记忆B细胞的编程了解得太少。使用现代疫苗配方，许多有希望的疫苗抗原无法引发保护性抗体。因此，我们对抗体亲和成熟的基本认识以及如何通过合理的蛋白质接种来增强不良的免疫原性仍然存在重大差距。研究重点：需要佐剂来使用基于蛋白质的疫苗配方诱导有效的抗体反应。滤泡辅助性T细胞（TFH）是一类新的免疫调节剂，专门控制记忆B细胞发育的多个阶段。在这里，我们研究了在初始启动和疫苗增强后抗原特异性TFH发展的先天细胞和分子调节因子。特定目的：利用新的单细胞策略，我们将剖析表达多肽mhcii的树突状细胞（DC）中控制抗原特异性TFH编程的分子成分。在抗原回忆后，我们现在发现记忆B细胞形成二次GC反应，重新多样化其表达的BCR，并有证据表明正在进行克隆选择。重要的是，在疫苗中添加二次佐剂促进了记忆B细胞反应中的亲和力成熟。这些最近的发现改变了BCR亲和成熟的主流观点，并指出了调节高亲和B细胞记忆（SA-2）的新的先天机制。影响：我们使用蛋白疫苗的多克隆小鼠模型和最先进的抗原特异性免疫功能的单细胞分析。这些对模型抗原的高分辨率研究有能力改变围绕现有疫苗范例的基本概念框架。重要的是，这些基本的新原理和检测方法可用于重新设计当代疫苗配方，以优化对更复杂抗原的高亲和力B细胞免疫。

DESCRIPTION (provided by applicant): Producing potent high-affinity antibodies that can neutralize target pathogens remains a central goal for vaccine research. While a great deal is known about antibody molecules themselves, still too little is understood about the programming of high-affinity memory B cells that produce them. Many promising vaccine antigens fail to elicit protective antibodies using contemporary vaccine formulations. Thus, major gaps remain in our basic understanding of antibody affinity maturation and how to enhance poor immunogenicity using rational protein vaccination. Research Focus: Adjuvants are required to induce potent antibody responses using protein-based vaccine formulations. Follicular helper T (TFH) cells are a new class of immune regulator specialized to control multiple stages of memory B cell development. Here, we examine the innate cellular and molecular regulators of antigen-specific TFH development at the point of initial priming and following the vaccine boost. Specific Aims: Using new single cell strategies, we will dissect the molecular components of regulatory programs within peptide MHCII-expressing dendritic cell (DC) that control antigen-specific TFH programming in vivo (SA-1). Upon antigen recall, we now reveal that memory B cells form secondary GC reactions, re-diversify their expressed BCR, with evidence for ongoing clonal selection. Importantly, addition of secondary adjuvant at the vaccine boost enhanced affinity maturation within the memory B cell response. These recent findings alter the prevailing view of BCR affinity maturation and indicate new innate mechanisms for regulating high-affinity B cell memory (SA-2). Impact: We use polyclonal murine models of protein vaccination with state-of-the-art single cell analyses of antigen-specific immune function. These high-resolution studies of model antigens have the capacity to shift the basic conceptual framework that surrounds existing vaccine paradigms. Importantly, these basic new principles and assays can be used to re-design contemporary vaccine formulations that optimize high-affinity B cell immunity to more complex antigens.