Antigen-specific NK cell memory

抗原特异性 NK 细胞记忆

• 批准号: 9925745
• 负责人: GEORGIA Doris TOMARAS
• 金额: $ 106.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925745
• 关键词: Affect; Anatomy; Antibodies; Antigen-Antibody Complex; Antigens; Antiviral Agents; Autoimmune Diseases; Binding; Blood; Cell Line; Cells; Cellular biology; Communicable Diseases; Cytolysis; Data; Dose; Effector Cell; Epigenetic Process; Epitopes; Exocytosis Induction; Expression Profiling; Fc Receptor; Gene Expression Profile; Genetic; Genetic Polymorphism; Genetic Transcription; Genotype; Grant; HIV; HIV-1; Human; Immune; Immune system; Immunoglobulin G; Immunology; Infection; Infusion procedures; Intervention; Israel; Learning; Letters; Location; Macaca mulatta; Mediating; Medical center; Memory; Modeling; Modification; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mucous Membrane; Natural Killer Cells; Nature; Outcome; Passive Immunization; Phagocytosis; Phenotype; Prevalence; Primates; Reporting; Role; SIV; Signal Transduction; Site; Specificity; Testing; Time; Tissues; Vaccines; Variant; Viral Antibodies; Virus; Work; base; biophysical analysis; cytokine; design; functional outcomes; glycosylation; improved; infection risk; neoplastic cell; neutralizing antibody; nonhuman primate; programs; protective efficacy; receptor expression; recruit; simian human immunodeficiency virus; vaccine response; vaccine trial

Traditionally natural killer (NK) cells are characterized as nonspecific effector cells, providing rapid recognition and lysis of virus-infected and neoplastic cells. However, recent work has shown that NK cells can demonstrate features of adaptive memory, including long-lived epigenetic modification intracellular γ-chain deficient (FcγR∆g) memory-like NK cells that require antibodies to grant antigen-specificity. Importantly, we have recently demonstrated for the first time evidence of antigen-specific NK cell memory in any primate species by characterizing HIV/SIV-specific NK cells in RM and showing an expansion of FcγR∆g NK cells in both HIV and SIV infections. Harnessing antibody mediated effector functions for HIV-1 vaccines will require a better understanding of effector cell biology, including the function and location (i.e. mucosal, systemic) of these newly identified memory-like NK cells and the interplay with FcR and Ig polymorphisms (with Project 1, 2). This Project will explore the specific hypothesis that polymorphisms in FcγRs (and Ig) in RM will modulate binding to memory natural killer cells and other effector cells thus influencing vaccine responses and subsequent protection against SHIV challenge. The specific aims for Project 3 are as follows: AIM 1: Determine FcγR expression and memory NK cell profiles in humans and RM. AIM 2: Determine functional differences between human and RM polymorphic FcγRs AIM 3: Perform a RM passive immunization study with defined FcγR genotypes/NK cell phenotype

传统上，自然杀伤 (NK) 细胞被称为非特异性效应细胞，可快速提供 然而，最近的研究表明 NK 细胞可以识别和裂解病毒感染的细胞和肿瘤细胞。 展示适应性记忆的特征，包括长寿命的表观遗传修饰细胞内 γ 链 需要抗体来赋予抗原特异性的缺陷（FcγRΔg）记忆样 NK 细胞。 最近首次证明了任何抗原特异性 NK 细胞记忆的证据 通过表征 RM 中的 HIV/SIV 特异性 NK 细胞并显示出 HIV 和 SIV 感染中的 FcγRΔg NK 细胞利用抗体介导的 HIV-1 效应功能。 疫苗需要更好地了解效应细胞生物学，包括功能和位置（即 这些新发现的记忆样 NK 细胞的粘膜、全身）以及与 FcR 和 Ig 的相互作用 多态性（与项目 1、2） 本项目将探讨多态性的具体假设。 RM 中的 FcγR（和 Ig）将调节与记忆自然杀伤细胞和其他效应细胞的结合，从而 疫苗反应和后续保护以防止影响 SHIV 挑战。 项目3如下： 目标 1：确定人类和 RM 中的 FcγR 表达和记忆 NK 细胞谱。 目标 2：确定人和 RM 多态性 FcγR 之间的功能差异 目标 3：使用明确的 FcγR 基因型/NK 细胞表型进行 RM 被动免疫研究