Human anti-viral immune responses in tissues and circulation

总体情况： 人类对病毒感染和疫苗接种的免疫反应涉及复杂的多尺度系统， 存在于组织中并在组织之间循环的许多不同的细胞群体。哥伦比亚重债穷国中心 已经建立了一个人类免疫学研究的框架，其中包括一个独特的组织资源， 淋巴、粘膜和外周组织从个体器官供体获得，疫苗组群治疗 免疫调节疗法，以及单细胞基因组学，成像和计算技术 生物学该中心的总体目标是获得人类先天性和适应性免疫细胞的深入概况 对病毒病原体（包括流感、CMV和SARS-CoV-2）和疫苗抗原的反应， 组织和循环，以提供对整个人体免疫反应的全面评估。 身体和年龄。在项目1（PI：D. Farber），我们将定量分析病毒类型的贡献， 组织、年龄和性别对人类抗病毒T细胞免疫的影响，并确定功能状态和克隆特征 不同组织部位的T细胞的单细胞分辨率。项目2（主要参与者：B。Reizis）将产生一个 组织和循环中人树突状细胞组成和功能的综合表征 抗病毒免疫反应和疫苗接种的背景。在项目3（PI：P. De Jager）中，我们将利用 一组接受分子靶向药物治疗的多发性硬化症患者， 以特定的方式对人群进行分类。通过对该队列进行多个周期的纵向随访， 疫苗接种与复杂的分子分析和单细胞分析，我们将回答基本的 关于循环和组织驻留淋巴细胞在维持T细胞功能中的作用的问题， 对疫苗的反应。所有这些项目都将得到五个核心的支持。行政核心将 协调中心之间和中心内部的沟通和协作，同时管理 中心单细胞核心将为单细胞基因组学提供最先进的协议和技术， 包括CITE-seq、scTCR-seq、scPLATE-seq，以及一种将抗原特异性与CITE- 单个T细胞的scTCR-seq和scTCR-seq称为TetTCR-seqHD。免疫测定和成像核心将 提供抗体的定量分析和用于空间分析的高维成像技术， 基因签名和细胞-细胞原位相互作用。临床核心将组织和患者队列 资源，向项目调查人员分发组织标本和血液。最后，数据管理和 分析核心（DMAC）将为系统级和单细胞分析提供创新的计算工具; 用于计算、数据存储和数据管理的基础设施;以及用于数据共享的工具，以确保 该中心的努力的影响。哥伦比亚重债穷国倡议将共同揭示人类免疫的新见解 并产生有价值的数据资源和参考地图，用于定义整个人类免疫反应。 身体和人类。

OVERALL: PROGRAM SUMMARY Human immune responses to viral infection and vaccination engage a complex, multi-scale system involving numerous diverse cellular populations residing in and circulating between tissues. The Columbia HIPC Center has established a framework for human immunology studies that includes a unique tissue resource where lymphoid, mucosal and peripheral tissue are obtained from individual organ donors, vaccine cohorts treated with immunomodulatory therapies, and technology for single-cell genomics, imaging, and computational biology. The overall goal of the Center is to obtain in-depth profiles of human innate and adaptive immune cells in response to viral pathogens (including influenza, CMV, and SARS-CoV-2) and vaccine antigens in both tissues and circulation, to provide a comprehensive assessment of the human immune response across the body and over age. In Project 1 (PI: D. Farber), we will quantitatively analyze the contributions of virus type, tissue, age, and sex on human anti-viral T cell immunity and define the functional states and clonal signatures of T cells in diverse tissue sites with single-cell resolution. Project 2 (PI: B. Reizis) will produce a comprehensive characterization of human dendritic cell composition and function in tissues and circulation in the context of anti-viral immune responses and vaccination. In Project 3 (PI: P. De Jager), we will leverage a cohort of multiple sclerosis patients treated with molecularly targeted drugs that selectively perturb immune populations in a compartment-specific fashion. By following this cohort longitudinally through multiple cycles of vaccination with sophisticated molecular profiling and single-cell analysis, we will answer fundamental questions about the role of circulating and tissue-resident lymphocytes in maintaining T cell function and responses to vaccines. All of these projects will be supported by five cores. The Administrative Core will coordinate inter- and intra-center communication and collaboration, while managing financial aspects of the Center. The Single Cell Core will provide state-of-the-art protocols and technologies for single-cell genomics, including CITE-seq, scTCR-seq, scPLATE-seq, and a new technique for linking antigen-specificity with CITE- seq and scTCR-seq of individual T cells called TetTCR-seqHD. The Immune Assay and Imaging Core will provide quantitative analysis of antibodies and high-dimensional imaging technologies for spatial analysis of gene signatures and cell-cell interactions in situ. The Clinical Core will organize tissue and patient cohort resources, distributing tissue specimens and blood to project investigators. Finally, the Data Management and Analysis Core (DMAC) will offer innovative computational tools for systems-level and single-cell analysis; infrastructure for computing, data storage, and data curation; and tools for data sharing to ensure the long-term impact of the Center’s efforts. Together, the Columbia HIPC will uncover new insights into human immunity and produce valuable data resources and reference maps for defining human immune responses across the body and the human population.