Innate Regulation of Adaptive Immunity

描述(申请人提供)：蛋白质亚单位疫苗是诱导长期免疫记忆的最安全的一般策略。在这些疫苗接种方案中，免疫的质量和数量由非特异性免疫佐剂决定。不幸的是，这些免疫佐剂如何在疫苗接受者身上发挥作用仍然知之甚少。我们已经开发了在小动物模型中研究免疫佐剂的新方法，以确定它们如何影响蛋白质抗原特异性的先天免疫、Th细胞和B细胞。这些方法将提供体内佐剂机制的信息，并帮助我们为未来的蛋白质疫苗设计改进的佐剂。获得性免疫的先天调节是目前这一应用的主要焦点。初始Th细胞对表达DC的外源多肽MHCII的特异性识别构成了Th细胞调节B细胞免疫发展的最早的“同源”检查点。我们最近提供的证据表明，Th细胞克隆选择是基于TCR-pMHCII亲和力的阈值水平。在初步研究中，我们发现在初始启动时改变免疫佐剂，实质上改变了TCR谱系的选择。这些数据使我们假设，佐剂以改变TCR选择阈值的方式控制DC的成熟和功能，影响效应器Th细胞功能的编程，并改变B细胞免疫的质量。我们将在两个具体目标上测试这一假设的各个方面。在第一个目标中，我们将使用一个高分辨率的动物模型来分析TCR谱系，以确定佐剂如何控制体内Th克隆选择和效应器功能的发展。在第二个目标中，我们建立了一个新的动物模型，以评估佐剂对pMHCII+DC的发育和功能的影响，以及这种影响对获得性免疫质量的影响。这些研究将有助于确定和改进体内的佐剂作用，并可能为新的佐剂和免疫疗法在预防和临床治疗传染病中确定新的分子靶点。

DESCRIPTION (provided by applicant): Protein sub-unit vaccines are the safest general strategy to induce long-term immune memory. In these vaccination regimens, the quality and quantity of immunity is determined by non-specific immune adjuvants. Unfortunately, how these immune adjuvants work in the vaccine recipient remains poorly understood. We have developed novel means for studying immune adjuvants in small animal models to determine how they impact innate immunity, Th cells and B cells specific for protein antigens. These approaches will provide information on the mechanism of adjuvanticity in vivo and help us to design improved adjuvants for future protein-based vaccines. Innate regulation of adaptive immunity is the primary focus of this current application. Specific recognition of foreign peptide-MHCII expressing DC by naive Th cells constitutes the earliest 'cognate' checkpoint in the development of Th cell regulated B cell immunity. We recently provided evidence that Th cell clonal selection is based on threshold levels of TCR-pMHCII affinity. In preliminary studies, we find that changing the immune adjuvant at initial priming, substantially alters TCR repertoire selection. These data led us to hypothesize that adjuvant controls DC maturation and function in ways that alter TCR selection thresholds, impact the programming of effector Th cell function, and alter the quality of B cell immunity. We will test aspects of this hypothesis across two specific aims. In the first aim, we will use an animal model with high resolution for the analysis of TCR repertoires to determine how adjuvant controls Th clonal selection and development of effector function in vivo. In the second aim, we develop a new animal model to evaluate the impact of adjuvant on the development and function of pMHCII+ DC and how this impacts the quality of the adaptive immunity. These studies will help to define and refine adjuvant action in vivo and may identify new molecular targets for novel adjuvants and immunotherapeutics in the preventative and clinical management of infectious disease.