Distinct contributions of CCR4 versus CCR7 to thymocyte localization and central tolerance

CCR4 与 CCR7 对胸腺细胞定位和中枢耐受的独特贡献

基本信息

批准号：
10265640
负责人：
Lauren Ilyse Richie EHRLICH
金额：
$ 95.17万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10265640
关键词：
Agonist Antigen Receptors Antigen-Presenting Cells Antigens Autoantigens Autoimmunity Automobile Driving Biological Assay Blood Bone Marrow CC chemokine receptor 4 CD69 antigen Cell Survival Cells Chimera organism Dangerousness Data Dendritic Cells Ensure Funding Genetic Impairment Individual Life Ligands Malignant Neoplasms Mature Thymocyte Mediating Modeling Molecular Mosaicism Peripheral Play Process Proteins Proteome Regulatory T-Lymphocyte Reporting Role Scanning Self Tolerance Structure of thymic medulla T cell receptor repertoire sequencing T-Lymphocyte T-cell receptor repertoire Testing Thymic epithelial cell Thymocyte Selection Thymus Gland Tissues autoreactive T cell autoreactivity base central tolerance chemokine receptor combat differential expression experimental study innovation mouse model novel pathogen prevent receptor expression thymocyte two photon microscopy

项目摘要

PROJECT ABSTRACT Some COVID-19 patients fare well, experiencing asymptomatic or mild disease, while up to 20% of patients have severe symptoms that can be fatal. Recent studies reveal elevated inflammatory cytokines and a reduced number of T cells in patients with severe disease, indicating that variation in immune responses may underlie differences in disease outcomes. However, features of protective versus pathologic immune responses to SARS- CoV-2 are not well understood. Furthermore, children tend to experience milder symptoms, while elderly individuals are more susceptible to severe disease, but it is not known if this is a function of age-associated differences in immune responses. In Aim 1, we propose to carry out paired single-cell transcriptomics, proteomics, and TCR repertoire sequencing of longitudinal blood samples from COVID-19 patients of different ages and disease severities in order to comprehensively profile the trajectory of immune responses to SARS- CoV-2 and identify candidate immune signatures that correlate with disease severity and age. Candidate signatures will be tested and refined in a larger patient cohort. Current vaccine efforts are focused on eliciting neutralizing antibodies against SARS-CoV-2. CD4+ T-cell responses are required to activate B cells to produce neutralizing antibodies and to support differentiation of CD8+ T cells, which can promote viral clearance and maintain immunologic memory. However, viral epitopes that activate protective T-cell responses remain unknown. In Aim 2, we will activate T cells from the longitudinal patient samples used for single-cell profiling in Aim 1 with “megapools” of overlapping peptides, spanning individual SARS-CoV-2 antigens. Activated T cells will be subjected to single-cell multi-omics analysis, allowing us to identify TCR sequences of clones that respond to each viral protein. Retrospective analysis of datasets from Aim 1 will enable us to follow the natural progression of these individual clones to evaluate frequencies and differentiation over the course of disease. Using these data, we will determine which viral antigens activate specific T-cell clones during effector and memory phases that correlate with favorable outcomes at each age, informing vaccine design. The increased incidence in autoimmune syndromes, such as the Kawasaki-like disease reported in pediatric patients, suggests that SARS- CoV-2 may induce autoimmunity; conversely, patients with autoimmune syndromes may be more susceptible to severe disease due to immune dysregulation. In Aim 3, we will explore both possibilities. Specifically, we will retrospectively determine if autoimmunity predisposes patients to severe disease and if autoimmune patients have more inflammatory T cell responses to SARS-CoV-2 antigens. We will also evaluate whether autoantigens with high sequence similarity to SARS-CoV-2 peptides activate a higher frequency of T cells in COVID-19 patients versus uninfected controls, and we will determine if COVID-19 patients develop autoantibodies. These studies will identify specific immune correlates of disease severity at each age to stratify patients into risk groups, inform vaccine design, and test links between autoimmunity and COVID-19 for informed clinical care.

项目摘要一些 COVID-19 患者状况良好，没有症状或病情较轻，而高达 20% 的患者患有最近的研究显示炎症细胞因子升高和减少。严重疾病患者的 T 细胞数量，表明免疫反应的变化可能是其背后的原因然而，针对 SARS 的保护性免疫反应与病理性免疫反应的特征存在差异。此外，对 CoV-2 的了解还不够深入，儿童的症状往往较轻，而老年人的症状往往较轻。个体更容易患严重疾病，但尚不清楚这是否与年龄相关在目标 1 中，我们建议进行配对单细胞转录组学，对来自不同国家的 COVID-19 患者的纵向血液样本进行蛋白质组学和 TCR 谱测序年龄和疾病严重程度，以全面描绘对 SARS 的免疫反应轨迹 CoV-2 并确定与疾病严重程度和年龄相关的候选免疫特征。签名将在更大的患者群体中进行测试和完善，目前的疫苗工作重点是引发。需要针对 SARS-CoV-2 的中和抗体来激活 B 细胞产生 CD4+ T 细胞反应。中和抗体并支持 CD8+ T 细胞的分化，从而促进病毒清除和然而，激活保护性 T 细胞反应的病毒表位仍然存在。在目标 2 中，我们将激活用于单细胞分析的纵向患者样本中的 T 细胞。目标 1 使用重叠肽的“巨型池”，涵盖单个 SARS-CoV-2 抗原。将进行单细胞多组学分析，使我们能够识别有反应的克隆的 TCR 序列对目标 1 的数据集进行回顾性分析将使我们能够遵循自然进展。使用这些个体克隆来评估疾病过程中的频率和分化。根据数据，我们将确定哪些病毒抗原在效应期和记忆期激活特定的 T 细胞克隆与每个年龄段的良好结果相关，为疫苗设计提供信息。自身免疫综合征，例如儿科患者报告的川崎样病，表明 SARS- CoV-2 可能会诱发自身免疫；相反，患有自身免疫综合征的患者可能更容易受到感染。在目标 3 中，我们将具体探讨这两种可能性。回顾性确定自身免疫是否会使患者易患严重疾病以及自身免疫患者是否对 SARS-CoV-2 抗原有更多的炎症 T 细胞反应我们还将评估是否存在自身抗原。与 SARS-CoV-2 肽具有高度序列相似性，在 COVID-19 中激活 T 细胞的频率更高患者与未感染的对照组进行比较，我们将确定 COVID-19 患者是否产生自身抗体。研究将确定每个年龄段疾病严重程度的特定免疫相关性，以将患者分为风险组，为疫苗设计提供信息，并测试自身免疫与 COVID-19 之间的联系，为临床护理提供信息。