Generation and Function of NK Cell Memory

NK细胞记忆的产生和功能

• 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
• 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

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成功和免疫治疗的关键。 感染和癌症，但携带免疫记忆的细胞也涉及许多人类 疾病T和B细胞被认为是免疫记忆的唯一载体，因此诊断， 治疗或预防免疫性疾病一直集中在这些淋巴细胞上。然而， 有证据表明，这种T和B细胞为中心的范式需要修改：初步工作表明，长寿命 记忆也可以通过肝脏驻留的自然杀伤（NK）细胞的离散子集获得， 淋巴结（LN）在遇到Ag呈递树突状细胞（DC）时的免疫应答。到目前为止，NK记忆体已经 四种不同的半抗原和六种病毒抗原。这个项目的目标是阐明 从机制上研究这种新型NK细胞功能并了解其病理生理学后果。两 具体目标将追求：目标1将研究记忆NK细胞的机制和后果， 在LN中预充。为此，我们将表征“幼稚”记忆能力NK细胞亚群， 研究提供Ag特异性的分子机制;我们将分析NK细胞的动力学 我们将探索人类NK细胞是否也可以获得记忆。目的2 将使用半抗原和流感病毒作为模型来表征引发的NK细胞的回忆应答。这里我们 将研究稳态和再激发时的记忆NK细胞运输;分析记忆NK细胞 流感病毒感染期间介导的保护;并探讨负共刺激在记忆NK细胞中的作用 细胞的生成、持久性和功能。