Natural killer cell receptor-expressing B cells as regulators of mucosal immunity in SIV infection

表达自然杀伤细胞受体的 B 细胞作为 SIV 感染粘膜免疫的调节剂

• 批准号: 9927204
• 负责人: Roger Keith Reeves
• 金额: $ 21万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-23 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927204
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Adaptive Immune System; Antiviral Agents; Autoimmune Diseases; B-Lymphocytes; Biological Markers; Cells; Cellular Assay; Characteristics; Chronic; Colon; Communicable Diseases; Custom; Cytometry; Data; Data Analyses; Disease; Genetic Transcription; HIV; HIV Infections; Health; Human; Immune; Immunoglobulin A; Immunoglobulin M; Immunologics; Immunotherapeutic agent; Infection; Inflammasome; Innate Immune Response; Innate Immune System; Interleukin-12; Interleukin-18; Knowledge; Lentivirus Infections; Lymphocyte; Lymphoid; Macaca mulatta; Mediating; Mediator of activation protein; Memory; Metabolic; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Myeloid Cells; Natural Immunity; Natural Killer Cells; Neighborhoods; Outcome; Pathogenicity; Pathway interactions; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Prevention strategy; Primates; Production; Publishing; Receptor Cell; Receptors, Antigen, B-Cell; Role; SIV; Sampling; Source; Spleen; Surface; Testing; Therapeutic; Tissues; Training; Vaccination; Vaccines; Virus; Virus Diseases; adaptive immune response; adaptive immunity; base; cell type; chronic infection; cross reactivity; cytokine; drug development; first responder; gastrointestinal; innate immune function; insight; macrophage; mast cell; monocyte; mucosal site; natural antibodies; neutrophil; new therapeutic target; nonhuman primate; novel; pathogen; phenotypic data; rectal; response; transcriptomics; transmission process; vaccine efficacy; vaginal mucosa

PROJECT SUMMARY Recently, a seemingly novel innate immune cell subset bearing features of natural killer (NK) and B cells was identified in mice. So-called NKB cells appear as first responders to viral infections at mucosal surfaces, but the full functional niche remains unknown and prior to our recent studies it has been unclear if these cells existed in higher order primates. In our recently published findings (Manickam et al., AIDS 2018) and new preliminary data we found that phenotypically analogous populations of NKB cells can be found systemically in humans and non-human primates, but are enriched in spleen, similar to mice. Furthermore, NKB cells had stable surface expression of non-secreted IgM and IgA, and are massively expanded in colonic tissues during chronic SIV infection. In this new proposal we will rigorously test we will test the overarching hypothesis that NKB cells are early responders at mucosal sites of infection and activation of this cell type is critical to initiate anti- HIV/SIV innate immune responses through two focused specific aims: (1) Identify transcriptomic and functional signatures of NKB cells under homeostatic conditions; and (2) Identify the role(s) and functional significance of mucosal NKB cells in SIV infection. The outcomes of this proposal will provide the first detailed analyses of NKB cells during lentivirus infection and potentially means to target these unique cells for immunotherapeutics or vaccine strategies.

项目概要 最近，一种看似新颖的先天免疫细胞亚群具有自然杀伤 (NK) 和 B 细胞的特征 在小鼠身上发现。所谓的 NKB 细胞似乎是粘膜表面病毒感染的第一反应者，但 完整的功能生态位仍然未知，在我们最近的研究之前，尚不清楚这些细胞是否存在于 高阶灵长类动物。在我们最近发表的研究结果（Manickam 等人，艾滋病 2018）和新的初步研究中 根据数据，我们发现表型相似的 NKB 细胞群体可以在人类和 非人类灵长类动物，但与小鼠类似，其脾脏含量丰富。此外，NKB细胞具有稳定的表面 非分泌型 IgM 和 IgA 的表达，并且在慢性 SIV 期间在结肠组织中大量扩增 感染。在这个新提案中，我们将严格测试 NKB 细胞的总体假设 感染粘膜部位的早期反应者和这种细胞类型的激活对于启动抗- HIV/SIV 先天免疫反应通过两个重点具体目标实现：(1) 识别转录组和 稳态条件下 NKB 细胞的功能特征； (2) 确定角色和 粘膜NKB细胞在SIV感染中的功能意义。该提案的结果将提供 对慢病毒感染期间 NKB 细胞的首次详细分析以及针对这些独特的潜在方法 用于免疫治疗或疫苗策略的细胞。