Project 2: Innate Immunity

免疫记忆是抗原特异性T和B淋巴细胞的标志。相比之下，先天免疫力 众所周知，该系统会启动快速的、非特异性的效应器反应，这些反应是短暂的。然而，最近的研究 提出了一种先天免疫系统中的免疫记忆，在这种记忆中，先天细胞可以 “记住”病原体会在几周到几个月的时间里遭遇。这种“训练有素的免疫力”现象 已有文献证明其与NK细胞有关，但对其在单核细胞和树突状细胞(DC)中的作用知之甚少。先天的 记忆被认为是通过髓系细胞的表观遗传变化来调节的，但有几个 关于先天记忆机制的基本问题。在这项提案中，我们将解决以下问题 关于接种17D(YFV-17D)或急性减毒黄热病活疫苗的问题 登革热病毒在人类中的感染，以及在小鼠身上的机制研究： 1.与记忆T细胞和B细胞不同，大多数DC和单核细胞亚群的寿命被认为是相对较短的 几天的时间。那么，由这种短暂的细胞获得的表观遗传变化如何调节先天记忆呢？ 在感染或接种后，髓系细胞亚群能持续几周吗？ 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造成的 (例如，通过旁分泌信号)，而不是天然细胞的固有属性，类似于经典的 记忆T细胞或B细胞表现出的免疫记忆现象？ 3.树突状细胞和单核细胞的反应是否增强(类似于适应性记忆反应 免疫系统)，在二次疫苗接种或感染期间？如果是这样的话，细胞和分子是什么 涉及的机制是什么？我们将从以下几个方面解决这些问题： 目的1.确定树突状细胞和单核细胞对 YFV-17D疫苗接种和人类登革热感染。 目的：检测YFV-17D疫苗免疫小鼠后DC和单核细胞的转化率。 人类，使用重水标签。 目的：探讨YFV-17D及其佐剂诱导小鼠先天性记忆的机制。 这些目标的成功完成将进一步加深我们对先天现象的机械性理解 记忆，并提供新的策略，诱导广泛和持久的保护，对各种病原体。

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.