High-resolution single cell profiling of vaccine responsiveness in the elderly

老年人疫苗反应性的高分辨率单细胞分析

• 批准号: 10092088
• 负责人: Jacques F Banchereau
• 金额: $ 56.75万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-14 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092088
• 关键词: Affect; Age; Aging; Antibody titer measurement; Antigen-Presenting Cells; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Biological Markers; Blood Cells; CD8-Positive T-Lymphocytes; Cells; Centers for Disease Control and Prevention (U.S.); Child; Chromatin; Clinical; Communicable Diseases; Cryopreservation; Custom; Cytometry; DNA Sequence Alteration; Data; Disease; Elderly; Enhancers; Event; Exposure to; Flow Cytometry; Functional disorder; Funding; Future; Gene Expression Profile; Generations; Genetic Transcription; Genomic approach; Genomics; Goals; Health; Helper-Inducer T-Lymphocyte; Heterogeneity; Human; IL7 gene; IL7R gene; Immune; Immune response; Immune system; Immunobiology; Immunologic Markers; Immunology; In Vitro; Individual; Infection; Inferior; Influenza; Influenza vaccination; Interferons; Interleukin-10; Knowledge; Light; Link; Molecular Profiling; Natural Immunity; Output; Pattern; Peripheral Blood Mononuclear Cell; Phenotype; Population; Positioning Attribute; Public Health; Research Personnel; Resolution; Resources; Role; Sampling; Signaling Protein; Succinates; Systemic Lupus Erythematosus; T-Lymphocyte Subsets; Testing; Time; Vaccinated; Vaccination; Vaccines; Work; adaptive immunity; analysis pipeline; cell type; cohort; comparative; design; flu; improved; influenza virus vaccine; interest; novel; potential biomarker; promoter; responders and non-responders; response; single cell analysis; single-cell RNA sequencing; transcriptome; transcriptomics; trivalent influenza vaccine; vaccine efficacy; vaccine response; young adult

PROJECT SUMMARY The goal of this project is to understand the aging-related genomic and functional changes in immune cells that affect responses to flu vaccination. The declining ability of the aging immune system to mount protective responses to vaccines is a major threat to the health, independence and survival of older adults. Much knowledge into the mechanisms of this decline has been gained from studies focused on one or a few immune cell subsets, or on bulk transcriptomics. However, this work has not produced two critical pieces of information: 1) an integrated view of the collective changes across relevant immune cell populations with aging, and 2) the ability to link specific immune cell subsets with their underlying cellular phenotypes/transcriptional profiles, and to compare these phenotypes and profiles as a function of age and responsiveness to vaccines. Single cell profiling, a term we use to encompass flow and mass cytometry together with single cell RNAseq (scRNAseq), is uniquely positioned to deconvolve immune system heterogeneity and identify novel distinct immune cell subsets in health and disease. Single cell profiling will therefore enable us to resolve the immune cell subset deficits relevant to the elderly immune response to vaccines from PBMCs, a highly heterogeneous starting population of cells, but one that offers the advantages of being clinically accessible, highly representative and ultimately unbiased for the purposes of data generation and analysis. We have shown that we can identify discreet cell-type-specific immune signatures of aging from PBMCs, even when such immune subsets represent a small fraction of the total PBMC pool, and have preliminary single cell profiling data from elderly PBMCs, underscoring feasibility. Here, we will analyze PBMCs at the single cell level from elderly donors before and after vaccination (Aim 1), and with or without in vitro activation of specific immune subsets (Aim 2), to understand the coordinated transcriptional and functional changes that occur, or fail to, as a function of age and vaccine responsiveness. This proposal builds on our recognized expertise in human immunology and incorporates essential expertise in cytometry and single cell transcriptomic analysis (JAX-GM), and access to elderly cohorts (George Kuchel, UConn Center on Aging). Impact: These studies will yield, with unprecedented resolution, the cell-type-specific immune signatures that distinguish responders to flu vaccine from non-responders, and will provide critical clues into the mechanisms and biomarkers of a successful vaccine immune response. Furthermore, these studies will generate a considerable amount of transcriptional and functional data related to the outputs of key innate immune and T/B-cell subsets involved in the influenza vaccine response of elderly individuals. The data will be an important resource for future studies of the elderly immune system in health and disease.

项目摘要 该项目的目的是了解免疫中与衰老相关的基因组和功能变化 影响对流感疫苗接种反应的细胞。衰老免疫系统安装的能力下降 对疫苗的保护性反应是对老年人健康，独立性和生存的主要威胁。很多 从一个或几种免疫的研究中获得了对这种下降机制的知识 细胞子集或大量转录组学。但是，这项工作并未产生两个关键信息： 1）对衰老的相关免疫细胞种群的集体变化的综合视图，2） 能够将特定免疫细胞亚群与其潜在的细胞表型/转录曲线联系起来的能力，并且 比较这些表型和特征是年龄和对疫苗的反应性的函数。单细胞 分析，我们用来包含流量和质量细胞术的术语以及单细胞RNASEQ（SCRNASEQ）， 独特地定位于解析免疫系统异质性并识别新型独特的免疫细胞 健康和疾病的子集。因此，单细胞分析将使我们能够解决免疫细胞子集 与PBMC对疫苗的老年免疫反应相关的缺陷，这是一种高度异质的开始 细胞群，但具有临床上可访问，高度代表性和的优势 最终出于数据生成和分析目的而公正。我们已经证明我们可以识别 谨慎的细胞类型特异性的PBMC衰老的免疫特异性特异性特异性免疫特征，即使这种免疫子群代表 总PBMC池的一小部分，并具有来自老年人PBMC的初步单细胞分析数据 强调可行性。在这里，我们将在以前和 疫苗接种后（AIM 1），并在有或没有体外激活特定的免疫子集（AIM 2），以了解 随着年龄和疫苗的函数的协调转录和功能变化 响应能力。该建议建立在我们公认的人类免疫学专业知识的基础上，并纳入了 细胞仪和单细胞转录组分析（JAX-GM）的基本专业知识，并进入老年人群 （乔治·库切尔（George Kuchel），UConn老化中心）。影响：这些研究将以前所未有的分辨率产生 细胞型特异性免疫特征，将流感疫苗与非反应者区分开，并将 为成功的疫苗免疫反应的机制和生物标志物提供关键线索。 此外，这些研究将产生与 关键先天免疫和T/B细胞子集的输出参与老年人的流感疫苗反应 个人。这些数据将是对健康中老年免疫系统的未来研究的重要资源， 疾病。