Innate Regulation of Adaptive Immunity

描述（由申请方提供）：蛋白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中起作用仍然知之甚少。我们已经开发了新的方法来研究小动物模型中的免疫佐剂，以确定它们如何影响蛋白抗原特异性的先天免疫、Th细胞和B细胞。这些方法将提供有关体内佐剂作用机制的信息，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本申请的主要焦点。幼稚Th细胞对表达外源肽-MHCII的DC的特异性识别构成Th细胞调节的B细胞免疫发展中最早的“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，我们发现在初始引发时改变免疫佐剂，实质上改变了TCR库选择。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成熟和功能，影响效应Th细胞功能的编程，并改变B细胞免疫的质量。我们将通过两个具体目标来检验这一假设的各个方面。在第一个目标中，我们将使用具有高分辨率的动物模型来分析TCR库，以确定佐剂如何控制Th克隆选择和体内效应器功能的发展。在第二个目标中，我们开发了一种新的动物模型来评估佐剂对pMHCII+ DC的发育和功能的影响以及这如何影响适应性免疫的质量。这些研究将有助于定义和完善佐剂在体内的作用，并可能确定新的佐剂和免疫治疗剂在预防和临床管理感染性疾病的新的分子靶点。

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.