Molecular Mechanisms of Adjuvant Triplet Combinations

翻译后摘要：佐剂三联体组合的分子机制 免疫系统对微生物输入的复杂组合做出反应。活疫苗 从病原体中经验性地减弱的疫苗是产生终身免疫的有力手段， 许多致命的病原体，因为它们模拟了对微生物信号组合的免疫反应。然而，在这方面， 使用免疫调节剂如佐剂的非活疫苗的合理设计仍然是一个 在活疫苗接种不有效或不可行的许多情况下，这是一项难以捉摸的任务，部分原因是 佐剂组合和解释串扰的相关分子机制仍然是一个主要的挑战。 基于我们最近的发现和广泛的初步数据，我们建议定义分子机制 通过其两种含有Toll样受体（TLR）、C-型凝集素受体（Lectin receptor） (CLR)、RIG-I样受体（RLR）和胞质dsDNA传感器（CDS）途径-诱导保护性CD 4+和CD 4 + T细胞， 小鼠中的CD 8 + T细胞应答。我们将使用一种创新的方法，即（i）比较-通过对比 佐剂三联体和匹配的单对和配对的定量效应作为精确定位分子的手段， 解释串扰的机制;和（ii）多尺度-通过研究在细胞，组织， 和整个身体。首先，我们将确定细胞内信号串扰的分子机制， 佐剂三联体通过在佐剂受体附近的蛋白质复合物水平上测试假设， 磷酸化级联和激酶-底物关系，以及基因调控网络。二是 确定佐剂组合影响细胞间信号传导的分子机制， 树突状细胞（DC）和T细胞， 表面和分泌的蛋白质组。第三，我们将检验关于佐剂三联体对肿瘤细胞增殖的影响的假设。 效应T细胞和记忆T细胞的生物体范围内的传播和播种，以及皮肤的底层细胞回路 （疫苗接种部位）和引流淋巴结，这解释了保护性长期T细胞免疫的诱导。 这项工作的结果将在佐剂组合研究的最前沿产生重要的见解， 表征佐剂的更高阶组合，其可以模拟良好建立的有效的活细胞免疫调节剂的作用， 减毒疫苗，并为未来的疫苗设计提供信息。

Abstract: Molecular Mechanisms of Adjuvant Triplet Combinations The immune system makes decisions in response to complex combinations of microbial inputs. Live vaccines that are empirically attenuated from pathogens have been a powerful means to yield life-long immunity against many deadly pathogens because they mimic immune responses to combinations of microbial signals. However, the rational design of non-live vaccines using immunomodulatory agents such as adjuvants has remained an elusive task in many cases where live vaccination is not efficacious or feasible, in part because identifying potent adjuvant combinations and associated molecular mechanisms that explain cross talk remains a major challenge. Based on our recent findings and extensive preliminary data, we propose to define the molecular mechanisms through which two adjuvant triplets – containing agonists for Toll-like receptor (TLR), C-type lection receptor (CLR), RIG-I-like receptor (RLR), and cytosolic dsDNA sensor (CDS) pathways – induce protective CD4+ and CD8+ T cell responses in mice. We will use an innovative approach which is (i) comparative – by contrasting the quantitative effects of adjuvant triplets and matching singles and pairs as means to accurately pinpoint molecular mechanisms explaining cross talk; and (ii) multiscale – by studying molecular mechanisms at play in cells, tissues, and the whole body. First, we will determine the molecular mechanisms of intra-cellular signaling cross talk by adjuvant triplets by testing hypotheses at the level of protein complexes proximal to adjuvant receptors, phosphorylation cascades and kinase-substrate relationships, and gene regulatory networks. Second, we will identify the molecular mechanisms through which adjuvant combinations impact inter-cellular signaling between dendritic cells (DCs) and T cells by testing hypotheses on the regulatory mechanisms shaping the cellular, surface, and secreted proteome of DCs. Third, we will test hypotheses on the effects of adjuvant triplets on the organism-wide spreading and seeding of effector and memory T cells, and the underlying cell circuits of the skin (vaccination site) and draining lymph node that explain the induction of protective, long-term T cell immunity. Results from this work will produce critical insights at the forefront of adjuvant combination research by characterizing higher-order combinations of adjuvants that can mimic the effects of well-established, potent live attenuated vaccines and inform future vaccine designs against infection.