Generation and Function of NK Cell Memory

NK细胞记忆的产生和功能

基本信息

批准号：
9319128
负责人：
ULRICH H VON ANDRIAN
金额：
$ 83.48万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319128
关键词：
Address Adoptive Transfer Antigen Receptors Antigen-Presenting Cells Antigens B-Cell Development B-Lymphocytes Book Chapters CXCR6 gene Cell Communication Cell physiology Cells Collaborations Contact hypersensitivity Dendritic Cells Diagnosis Frequencies Funding Future Gene Proteins Generations Genes Genetic Genetic Recombination Goals Haptens Hepatic Heritability Homing Human Immune System Diseases Immune response Immunologic Memory Immunologics Immunology Immunotherapy Infection Influenza J segment gene Knockout Mice Learning Legal patent Liver Lymphocyte Mediating Memory Modeling Molecular Mus Natural Killer Cells Paper Pathway interactions Peripheral Phenotype Population Prions Process Property RAG1 gene Recruitment Activity Role SCID Mice Signal Transduction Site Source Specificity Spleen T-Lymphocyte Testing Tissues Vaccines Viral Viral Antigens Virus Virus Diseases Work adaptive immune response adaptive immunity antiviral immunity base cancer cell chemokine receptor editorial exhaustion experience human disease infectious disease treatment influenzavirus innate immune function intravital microscopy lymph nodes macrophage mast cell multi-photon novel offspring pathogen prevent receptor residence response sample fixation success trafficking vaccine development virtual

项目摘要

The formation of antigen (Ag)-specific memory is key for the success of vaccines and for immunotherapy of infections and cancer, but the cells that carry immunological memory are also implicated in numerous human disease. T and B cells have been considered sole carriers of immunological memory, so efforts to diagnose, treat or prevent immune diseases have been focused on these lymphocytes. However, there is mounting evidence that this T and B cell-centric paradigm requires revision: preliminary work has shown that long-lived memory can also be acquired by a discrete subset of liver-resident natural killer (NK) cells, which arise in lymph nodes (LNs) upon encounter of Ag presenting dendritic cells (DCs). To date, NK memory has been documented for four distinct haptens and six viral Ags. The goals of this project are to elucidate mechanistically this novel NK cell function and to understand its pathophysiological consequences. Two specific aims will be pursued: Aim 1 will investigate the mechanisms and consequences of memory NK cell priming in LNs. To this end, we will characterize the 'naive' memory-capable NK cell subset(s) and investigate the molecular mechanism that provides Ag-specificity; we will analyze the dynamics of NK cell interactions with DCs In LNs; and we will explore whether human NK cells can also acquire memory. Aim 2 will characterize recall responses of primed NK cells using haptens and influenza virus as models. Here, we will investigate memory NK cell trafficking at steady state and upon rechallenge; analyze memory NK cell mediated protection during influenza infection; and explore the role of negative costimulation in memory NK cell generation, persistence and function.

抗原（Ag）特异性记忆的形成是疫苗和免疫治疗成功的关键感染和癌症，但携带免疫记忆的细胞也与许多人类疾病有关疾病。 T 细胞和 B 细胞被认为是免疫记忆的唯一载体，因此努力诊断、治疗或预防免疫疾病的重点一直集中在这些淋巴细胞上。然而，有安装有证据表明这种以 T 细胞和 B 细胞为中心的范式需要修改：初步工作表明，长寿命肝脏驻留的自然杀伤 (NK) 细胞的离散子集也可以获得记忆，这些细胞产生于淋巴结（LN）遇到Ag呈递树突状细胞（DC）时。迄今为止，NK记忆已记录了四种不同的半抗原和六种病毒抗原。该项目的目标是阐明从机制上了解这种新型 NK 细胞的功能并了解其病理生理学后果。二将追求特定目标：目标 1 将研究记忆 NK 细胞的机制和后果在 LN 中启动。为此，我们将表征“幼稚”的具有记忆能力的 NK 细胞子集，并研究提供Ag特异性的分子机制；我们将分析NK细胞的动态与 LN 中的 DC 进行交互；我们将探索人类NK细胞是否也能获得记忆。目标2 将使用半抗原和流感病毒作为模型来表征引发的 NK 细胞的回忆反应。在这里，我们将研究稳态和再次挑战时的记忆 NK 细胞贩运；分析记忆 NK 细胞流感感染期间的介导保护；并探讨负性共刺激在记忆NK中的作用细胞的生成、持久性和功能。