Mechanisms of Innate Immune Memory

描述（由申请人提供）：本申请提出了一个5年计划，为候选人提供指导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疗中心的独立医生-科学家，研究先天免疫反应和增强这种免疫系统治疗儿科疾病的潜在机制。拟议的工作将在圣路易斯的华盛顿大学进行，由韦恩横山博士指导，他是一位有成就的免疫学家和医学科学家。对感染的免疫应答由两大类介导，即先天免疫系统和适应性免疫系统。先天免疫和适应性免疫之间的一个经典区别是免疫记忆对适应性T和B淋巴细胞的限制。先天免疫细胞是抵抗病原体的第一线防御，并且被认为对感染有一致的反应，而不管先前的暴露，即，它们不表现出对先前激活的记忆。自然杀伤（NK）细胞是能够识别和杀伤靶细胞并产生免疫调节细胞因子（尤其是IFN-？）的先天性淋巴细胞。NK细胞对于多种病原体的初始控制是重要的，并且NK细胞的缺陷导致不受控制的致命感染。利用过继性转移系统的初步研究表明，NK细胞的历史，以前的细胞因子活化表现出NK细胞的内在，增强能力，产生IFN-？在再刺激时。这种“类似记忆”的特性似乎既稳定又可遗传。本实验将进一步研究记忆样NK细胞的体内外特性，并探讨NK细胞记忆的机制。具体目标是：（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细胞是否响应病原体在体内分化;（3）确定增强的IFN-？记忆样NK细胞的产生是通过转录、表观遗传修饰和/或转录后控制的。这些研究具有临床相关性，因为适应性免疫系统不成熟或功能障碍的患者，如新生儿或免疫功能低下的患者，可能受益于其完整的先天免疫NK细胞应答的增强。自然杀伤细胞是先天免疫反应的关键组成部分，并提供针对各种感染的保护。这些实验探索了自然杀伤细胞和先天免疫系统可以根据先前的经验增强的基本机制。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.