Mechanisms of Innate Immune Memory

描述(由申请者提供)：本申请提出一个为期5年的计划，为候选人提供有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一名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这种免疫系统用于治疗儿科疾病的潜在机制。这项拟议的工作将在圣路易斯的华盛顿大学进行，由杰出的免疫学家、内科科学家韦恩·横山博士指导。对感染的免疫反应由两条宽大的手臂介导，即先天免疫系统和获得性免疫系统。天然免疫和获得性免疫之间的一个经典区别是免疫记忆仅限于适应性T和B淋巴细胞。先天性免疫细胞是抵御病原体的第一线防御细胞，被认为对感染做出一致的反应，无论以前接触过什么，也就是说，它们不表现出对先前激活的记忆。自然杀伤细胞(NK细胞)是一种天然的淋巴细胞，能够识别和杀伤靶细胞，并产生免疫调节细胞因子，特别是干扰素？NK细胞对各种病原体的初始控制很重要，而NK细胞缺陷会导致无法控制的、致命的感染。采用过继转移系统的初步研究表明，有细胞因子激活史的NK细胞表现出NK固有的、产生干扰素？的增强能力。在重新刺激的时候。这种“记忆般的”属性似乎既是稳定的，也是可遗传的。这些实验将在体外和体内进一步研究类记忆NK细胞的特性，并探讨NK细胞记忆的机制。其具体目的是：(1)确定记忆样NK细胞的功能属性以及是否能产生细胞毒性记忆样NK细胞；(2)确定记忆样NK细胞是否在体内分化以响应病原体；以及(3)确定是否增强了干扰素？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障碍的患者，如新生儿或免疫低下患者，可能受益于其完整的天然免疫NK细胞反应的增强。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。这些实验探索了根据先前的经验可以增强自然杀伤细胞和先天免疫系统的基本机制。这一领域的研究可能导致改进的治疗方法，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.