权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of immune receptor clustering in controlling efficacy of antibody-dependent FcγRIIIa-mediated cytotoxicity by NK cells

免疫受体簇在控制 NK 细胞抗体依赖性 FcγRIIIa 介导的细胞毒性中的作用

基本信息

批准号：
10544158
负责人：
Kerry S Campbell
金额：
$ 50.26万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544158
关键词：
Affect Affinity Antibodies Antigens Autoimmune Diseases Avidity Binding CD8-Positive T-Lymphocytes CD8B1 gene Cell Adhesion Molecules Cell Degranulation Cell Maturation Cell surface Cells Communicable Diseases Cytolysis Cytoplasmic Granules Cytotoxic T-Lymphocytes Data Development Diffusion Disease Dissociation Effector Cell Environment FCGR3B gene Fab Immunoglobulins Fc Immunoglobulins Goals Host Defense Human IgG1 IgG3 Immunoglobulin G Immunologic Receptors Immunotherapeutic agent Immunotherapy Infection Integrins Intercellular adhesion molecule 1 Kinetics Ligands Ligation Lipid Bilayers Lymphocyte MHC Interaction MS4A1 gene Malignant Neoplasms Mediating Meditation Membrane Modeling Molecular NK Cell Activation Names Natural Killer Cell Immunotherapy Natural Killer Cell toxicity Natural Killer Cells Nature Peptide/MHC Complex Play Positioning Attribute Production Productivity Proteins Receptor Cell Role Signal Induction Signal Transduction Structure Surface Synapses System T cell response T-Lymphocyte Testing Therapeutic Variant Virus Virus Diseases antibody-dependent cell cytotoxicity cancer cell cell killing crosslink cytokine cytotoxic cytotoxicity density design immune function immunological synapse formation improved kinetic model membrane model nanocluster nanolipoprotein particles nanoparticle nanoscale novel strategies pathogen receptor receptor-mediated signaling response rituximab synaptic function synaptogenesis tool tumor

项目摘要

Project Summary NK cells are capable of killing virus-infected and cancer cells and, therefore, play an important role in innate host defense. Unlike cytotoxic T lymphocytes (CTL), whose cytolytic activity is induced by productive TCR engagement with cognate pMHC ligands, activation of NK cells is regulated by a set of activating and inhibitory receptors. The net result of the signals induced by these receptors determines the extent of NK cell effector activities such as INF-γ production and granule-mediated cytotoxicity. One of the main mechanisms of NK cell- mediated cytolytic activity depends on antibodies and is termed antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is induced by FcγRIIIa (CD16) receptors that do not directly recognize antigens on the target cells, but interact with Fc fragments of IgG antibodies specifically bound to the antigens on the surface of target cells. Available evidence, including ours, strongly suggests that ligand-mediated clustering of activating receptors on cytotoxic lymphocytes regulates kinetics of intracellular signaling, formation of a highly ordered synaptic interface, kinetics of granule delivery, and efficiency of target cell lysis (1-6). The receptor clustering can be further modulated by antigen co-clustering with other membrane ligands on target cells, which interact with inhibitory receptors or adhesion molecules on the surface of NK cells. We hypothesize that differences in FcγRIIIa (CD16) clustering/co-clustering could have significant impact on receptor-mediated signaling influencing efficiency of ADCC. Thus, the goal of this project is to study how homotypic and heterotypic ligand clustering regulates ability of the ligands to cooperate in the engagement of CD16, inhibitory receptors and adhesion molecules to modulate efficiency of ADCC. We will use well-characterized CD16.NK92 cells that we have developed to model functions of NK cells (7-12) and freshly activated human NK cells to investigate the role of CD16 clustering/co-clustering with other receptors. To achieve this goal, we will exploit fluorescent nanoparticles (NiNLPs) that can be loaded with ligands for CD16, adhesion molecules, and inhibitory receptors at various ratios and densities, and will examine the binding kinetics of these model membrane clusters to NK cells as well as the kinetics of induced intracellular Ca2+ signaling. We will also utilize planar lipid bilayers presenting the same ligands, either dispersed in the bilayers or co-localized by cross-linking with the iDimerize system, and will analyze how cross-linking of the ligands will influence structure of the synaptic interface and the kinetics of NK cell degranulation. The expected results will provide significantly improved understanding of the mechanisms controlling cytolytic activity of primary and activated human NK cells to design new NK cell-based immunotherapeutic strategies to improve efficiency of ADCC to treat viral infections, autoimmune diseases, and cancer.

项目总结