Project 2: Innate Immunity

免疫记忆是抗原特异性T和B淋巴细胞的标志。相反，先天免疫 已知该系统启动快速的、非特异性的效应子应答，其是短暂的。但最近的研究 提出了先天免疫系统中的一种免疫记忆形式，先天细胞可以 “记住”病原体遭遇数周至数月。这种“训练免疫力”的现象 在NK细胞中有记载，但对其在单核细胞和树突状细胞（DC）中的作用知之甚少。先天 记忆被认为是通过骨髓细胞中的表观遗传变化介导的，但有几个 关于先天记忆机制的基本问题。在本提案中，我们将处理以下问题 接种黄热病减毒活疫苗17 D（YFV-17 D）或急性 在人类中的登革热病毒感染，以及在小鼠中的机制研究中： 1.与记忆T和B细胞不同，大多数DC和单核细胞亚群被认为具有相对较短的寿命 几天后那么，这种短命细胞获得的表观遗传变化是如何介导先天记忆的呢？ 感染或接种疫苗后，髓源性细胞亚群能否持续数周？ 2.所谓的“先天记忆”在多大程度上是由持续的适应性免疫反应引起的 (for例如，通过旁分泌信号），与先天细胞的细胞固有特性，类似于经典的 记忆T或B细胞表现出的免疫记忆现象？ 3.是否存在DC和单核细胞的增强反应（类似于适应性免疫中的记忆反应）， 免疫系统），在二次接种或感染？如果是这样的话， 涉及的机制？我们将按照以下目标处理这些问题： 目标1.确定DCs和单核细胞响应于 YFV-17 D疫苗接种和人类登革热感染。 目的2：确定DCs和单核细胞对YFV-17 D疫苗接种的应答转换率。 人类，使用重水标记。 目的3：探讨YFV-17 D及其佐剂诱导小鼠先天记忆的机制。 这些目标的成功实现将进一步加深我们对先天性遗传现象的机械理解。 记忆，并提供新的策略，诱导广泛和持久的保护，对不同的病原体。

Immunological memory is a hallmark of antigen-specific T and B lymphocytes. In contrast, the innate immune system is known to launch rapid, non-specific effector responses, which are short-lived. However, recent studies have proposed a form of immunological memory in the innate immune system, where innate cells can “remember” a pathogen encounter for several weeks to months. This phenomenon of “trained immunity” has been documented for NK cells, but less is known about its role in monocytes and dendritic cells (DCs). Innate memory has been suggested to be mediated via epigenetic changes in myeloid cells, but there are several fundamental questions about the mechanisms of innate memory. In this proposal, we will address the following questions in the context of vaccination with the live attenuated yellow fever vaccine 17D (YFV-17D) or acute dengue viral infection in humans, and in mechanistic studies in mice: 1. Unlike memory T and B cells, most DC and monocyte subsets are believed to have a relatively short lifespan of a few days. So how can epigenetic changes acquired by such short-lived cells mediate innate memory? Can subsets of myeloid-derived cells persist for several weeks after infection or vaccination? 2. To what extent is so called “innate memory” caused by the effects of an ongoing adaptive immune response (for example, via paracrine signaling), versus a cell intrinsic property of innate cells, similar to the classic phenomenon of immune memory exhibited by memory T or B cells? 3. Is there an enhanced response of DCs and monocytes, (similar to a memory response in the adaptive immune system), during secondary vaccination or infection? If so, what are the cellular and molecular mechanisms involved? We will address these questions in the following aims: Aim 1. Determining the innate response and regulatory landscape of DCs and monocytes in response to YFV-17D vaccination and dengue infection in humans. Aim 2: To determine the turnover rates of DCs and monocytes in response to YFV-17D vaccination in humans, using heavy water labeling. Aim 3: To define the mechanisms of innate memory induced by YFV-17D and adjuvants. Successful completion of these aims will further our mechanistic understanding of the phenomenon of innate memory, and offer novel strategies inducing broad and durable protection against diverse pathogens.