Determinants of antigen specific CD4 T cell function in tuberculosis

结核病中抗原特异性 CD4 T 细胞功能的决定因素

基本信息

批准号：
10255840
负责人：
Tyler Dallas Bold
金额：
$ 20.11万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10255840
关键词：
Active Sites Activities of Daily Living Affinity Antigen Targeting Antigens Binding Blood CD4 Positive T Lymphocytes CRISPR interference Cause of Death Cell physiology Cells Cerebrospinal Fluid Characteristics Collaborations Communicable Diseases Cryopreserved Cell Data Development Disease Epitopes Flow Cytometry Fluorescence Funding Future Gene Expression Genetic Transcription Genomics Goals HIV Human Immune Immunity Immunology Impairment Individual Infection Interferon Type II International Intrinsic factor Medicine Meningeal Tuberculosis Mentors Mentorship Minnesota Mus Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Pathogenesis Peptides Physicians Population Population Heterogeneity Positioning Attribute Program Development Reporter Research Scientist Signal Transduction Site Sorting - Cell Movement Specimen Stimulus T cell response T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Testing Training Training Activity Tuberculosis Tuberculosis Vaccines Uganda Universities Work base career development cell type cytokine design experience global health high dimensionality human subject immune function in vivo innovation mouse model novel novel strategies novel vaccines patient oriented research professor recruit response single-cell RNA sequencing skills stem tool training opportunity transcriptomics translational research program tuberculosis immunity vaccine candidate vaccine development

项目摘要

This proposal presents a five-year research career development program focused on the study of antigen specific CD4 T cells in tuberculosis (TB), with the long-term goals to reveal new information about immune protection in TB and inform the development of an effective new vaccine for this disease. The candidate is currently an Assistant Professor of Medicine at the University of Minnesota (UMN) in the Division of Infectious Diseases. The outlined proposal builds on the candidate’s previous experience by adding new domains of expertise in advanced T cell immunology, international collaborative patient-oriented research and human immunology, and single cell transcriptomics. The training objectives are represented by the mentorship team of Marc Jenkins and David Boulware, and other key collaborators at UMN. The proposed experimental and didactic work will position the candidate with a unique set of cross-disciplinary skills that will enable his transition to independence as a physician scientist focused on the immunology of TB. A better understanding of the factors that govern CD4 T cell function in TB could help guide the development of vaccine candidates more likely to elicit protective immunity against TB disease. It is becoming clearer that IFN-g secretion is only one protective function of CD4 T cells in TB. The other key effector mechanisms of CD4 T cells in TB are still being defined, and the determinants of these immune functions remain to be fully characterized. The overall scientific objectives of this particular project are to characterize CD4 T cell functions at the site of infection and to define how antigen availability and T cell receptor (TCR)- epitope affinity govern these functions. The premise of this proposal is that effector activity of CD4 T cells at the site of TB infection is determined by characteristics of the Mtb antigen targeted. The central hypotheses are 1) that CD4 T cells with lower affinity TCRs, targeting Mtb antigens with moderate abundance, have more diverse and superior functions, and 2) that antigen specific CD4 T cells at the site of infection perform key effector functions outside the Th1 paradigm. To test these hypotheses, the following aims are proposed: Aim 1: Determine how antigen-intrinsic factors govern CD4 T cell function in TB, and Aim 2: Characterize CD4 T cell function and diversity at the site of human TB infection. To accomplish these aims, innovative approaches are proposed including: modulation of Mtb gene expression in vivo, identification of lower affinity TCRs, and unbiased identification of CD4 T cells that have recently received TCR stimulation in vivo. By pairing these approaches in the mouse model with studies of human T cells from the cerebrospinal fluid of individuals with HIV-associated TB meningitis, using single cell transcriptomic profiling, these studies will characterize how Mtb antigen-intrinsic factors elicit CD4 T cell populations of varying functional capacity and diversity. This K08 project will guide new TB vaccine development and promote the candidate’s transition to independence.

该提案提出了一个为期五年的研究职业发展计划，重点关注抗原研究结核病 (TB) 中的特异性 CD4 T 细胞，长期目标是揭示有关免疫的新信息保护结核病并为开发针对该疾病的有效新疫苗提供信息。目前是明尼苏达大学 (UMN) 传染病科的医学助理教授概述的提案以候选人之前的经验为基础，增加了新的领域。先进 T 细胞免疫学、以患者为中心的国际合作研究和人类研究方面的专业知识培训目标由导师团队代表。马克·詹金斯 (Marc Jenkins) 和大卫·博尔韦尔 (David Boulware) 以及 UMN 的其他主要合作者提出的实验和建议。教学工作将使候选人具备一套独特的跨学科技能，使他能够作为一名专注于结核病免疫学的医师科学家，过渡到独立。更好地了解结核病中控制 CD4 T 细胞功能的因素可能有助于指导候选疫苗的开发更有可能引发针对结核病的保护性免疫力。更清楚的是，IFN-g 分泌只是 CD4 T 细胞在结核病中的一种保护功能，另一个关键效应器。 CD4 T 细胞在结核病中的作用机制仍在研究中，这些免疫功能的决定因素该特定项目的总体科学目标仍有待充分表征。 CD4 T 细胞在感染部位发挥作用，并确定抗原可用性和 T 细胞受体 (TCR) 的作用- 表位亲和力控制着这些功能，这一提议的前提是 CD4 T 细胞的效应活性。结核病感染部位由靶向结核分枝杆菌抗原的特征决定。中心假设是。 1) 具有较低亲和力 TCR 的 CD4 T 细胞，针对中等丰度的 Mtb 抗原，具有更多多样化且卓越的功能，2) 感染部位的抗原特异性 CD4 T 细胞发挥关键作用为了检验这些假设，提出了以下目标： 1：确定抗原内在因素如何控制 TB 中的 CD4 T 细胞功能，目标 2：表征 CD4 T 为了实现这些目标，需要创新的方法。提议的内容包括：体内 Mtb 基因表达的调节、低亲和力 TCR 的鉴定，以及通过将这些细胞配对，公正地识别最近在体内接受过 TCR 刺激的 CD4 T 细胞。在小鼠模型中研究来自患有这种疾病的个体的脑脊液中的人类 T 细胞 HIV 相关结核性脑膜炎，使用单细胞转录组分析，这些研究将描述 Mtb 如何抗原内在因素引发具有不同功能能力和多样性的 CD4 T 细胞群。项目将指导新的结核病疫苗开发并促进候选人向独立过渡。