Mechanisms of Innate Immune Memory

描述（由申请人提供）：该申请提出了一个为期5年的计划，为候选人提供指导的科学培训和职业发展指导。候选人的长期目标是成为学术医学中心的独立内科科学家，研究先天性免疫反应和增强儿童免疫系统治疗儿科疾病的潜在机制。这项工作将在圣路易斯的华盛顿大学进行，由免疫学家、内科科学家韦恩·横山博士指导。对感染的免疫反应是由先天免疫系统和适应性免疫系统这两条大臂介导的。先天免疫和适应性免疫的一个经典区别是免疫记忆对适应性T淋巴细胞和B淋巴细胞的限制。先天免疫细胞是对抗病原体的第一道防线，被认为对感染的反应是一致的，无论以前的暴露情况如何，也就是说，它们不表现出先前激活的记忆。自然杀伤细胞（NK）是一种先天淋巴细胞，能够识别和杀死靶细胞，并产生免疫调节细胞因子，特别是IFN-？NK细胞对各种病原体的初始控制很重要，NK细胞的缺陷会导致无法控制的致命感染。利用过继转移系统的初步研究表明，具有先前细胞因子激活历史的NK细胞表现出NK固有的增强的产生IFN-？再刺激。这种“类似记忆”的特性似乎既稳定又可遗传。本实验将进一步在体外和体内对记忆样NK细胞进行表征，并研究NK细胞记忆的机制。具体目的是：(1)确定记忆样NK细胞的功能属性，以及是否可以产生细胞毒性记忆样NK细胞；(2)确定记忆样NK细胞是否在体内对病原体的反应中分化；(3)确定IFN-？记忆样NK细胞的产生受转录、表观遗传修饰和/或转录后调控。这些研究具有临床意义，因为适应性免疫系统不成熟或功能失调的患者，如新生儿或免疫功能低下的患者，可能受益于增强其完整的先天免疫NK细胞反应。自然杀伤细胞是先天免疫反应的关键组成部分，并提供对各种感染的保护。这些实验探索了基于先前经验的自然杀伤细胞和先天免疫系统可能增强的基本机制。这一领域的研究可能会导致改进的疗法，以增强免疫反应和治疗感染。

DESCRIPTION (provided by applicant): This application proposes a 5 year program to provide the candidate with mentored scientific training and career development guidance. The long term goal of the candidate is to be an independent physician-scientist at an academic medical center, investigating the innate immune response and potential mechanisms of enhancing this immune system for the treatment of pediatric disease. The proposed work will be performed at Washington University in St. Louis under the mentorship of Dr. Wayne Yokoyama, an accomplished immunologist and physician-scientist. The immune response to infection is mediated by two broad arms, the innate and adaptive immune systems. One classical distinction between innate and adaptive immunity is the restriction of immunologic memory to adaptive T and B lymphocytes. Innate immune cells are a first-line defense against pathogens and are thought to respond consistently to infection, regardless of previous exposure, i.e., they do not exhibit memory of prior activation. Natural killer (NK) cells are innate lymphocytes capable of recognizing and killing target cells and producing immunoregulatory cytokines, especially IFN-?. NK cells are important for the initial control of a variety of pathogens, and defects in NK cells lead to uncontrolled, fatal infections. Preliminary studies utilizing an adoptive transfer system demonstrate that NK cells with a history of prior cytokine activation exhibit an NK-intrinsic, enhanced capacity to produce IFN-? upon re- stimulation. This "memory-like" property appears to be both stable and heritable. The proposed experiments will further characterize memory-like NK cells in vitro and in vivo and investigate the mechanisms of NK cell memory. The specific aims are to: (1) Determine the functional attributes of memory-like NK cells and if cytotoxic memory-like NK cells can be generated; (2) Determine if memory-like NK cells differentiate in vivo in response to pathogens; and (3) Determine if enhanced IFN-? production by memory-like NK cells is controlled transcriptionally, by epigenetic modifications, and/or post-transcriptionally. These studies have clinical relevance, since patients whose adaptive immune systems are immature or dysfunctional, such as neonates or immunocompromised patients, may benefit from augmentation of their intact innate immune NK cell response. Natural killer cells are a key component of the innate immune response and provide protection against a variety of infections. These experiments explore fundamental mechanisms by which natural killer cells and the innate immune system may be enhanced based on prior experiences. This area of research may lead to improved therapies to augment the immune response and treat infections.