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

• 批准号: 10200461
• 负责人: Lauren Ilyse Richie EHRLICH
• 金额: $ 96.32万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200461
• 关键词: 2019-nCoV; Address; Adult; Adult Respiratory Distress Syndrome; Age; Antigens; Antiviral Agents; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bioinformatics; Biological Assay; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; Categories; Cells; Child; Childhood; Clinical; Clone Cells; Coronavirus; Data; Data Set; Disease; Disease Outcome; Disease Progression; Elderly; Enrollment; Epitopes; Evaluation; Exanthema; Fever; Frequencies; Goals; Immune; Immune response; Immunologic Memory; Incidence; Individual; Infection; Inflammatory; Inflammatory Response; Lead; Link; Longevity; Longitudinal cohort; Memory; Molecular; Outcome; Pathogenicity; Pathologic; Pathology; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Pneumonia; Prevalence; Proteins; Proteomics; Reporting; Research; Risk; Sampling; Severities; Severity of illness; Specificity; Symptoms; Syndrome; T cell response; T-Lymphocyte; T-cell receptor repertoire; Testing; Vaccine Design; Vaccines; Variant; Viral; Viral Antigens; Viral Proteins; adaptive immune response; adaptive immunity; age group; austin; autoinflammatory; biobank; cell type; central tolerance; clinical care; cohort; cytokine; cytokine release syndrome; experience; individual patient; individual variation; mimicry; multiple omics; neutralizing antibody; nonhuman primate; older patient; patient stratification; pediatric patients; programs; prospective; recruit; thymocyte; transcriptomics

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 一些新冠肺炎患者进展良好，经历无症状或轻度疾病，而高达20%的患者有 可能致命的严重症状。最近的研究显示炎性细胞因子升高和 重症患者的T细胞数量，表明免疫反应的差异可能是 疾病结局的差异。然而，针对SARS的保护性免疫反应与病理性免疫反应的特征- 对CoV-2的了解还不是很清楚。此外，儿童往往症状较轻，而老年人 个人更容易患上严重的疾病，但尚不清楚这是否与年龄有关 免疫反应的差异。在目标1中，我们建议进行配对的单细胞转录转录， 不同类型新冠肺炎患者纵向血样蛋白质组学及TCR谱分析 年龄和疾病严重程度，以全面描绘SARS免疫反应的轨迹- 并确定与疾病严重程度和年龄相关的候选免疫特征。侯选人 签名将在更大的患者队列中进行测试和改进。目前的疫苗努力集中在引出 抗SARS-CoV-2的中和抗体。需要CD4+T细胞反应来激活B细胞以产生 中和抗体，并支持CD8+T细胞的分化，这可以促进病毒清除和 保持免疫记忆。然而，激活保护性T细胞反应的病毒表位仍然存在 未知。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由重叠的多肽组成的“巨型池”，跨越单个SARS-CoV-2抗原。激活的T细胞 将接受单细胞多组学分析，使我们能够识别响应的克隆的TCR序列 对每一种病毒蛋白。对来自目标1的数据集的回顾分析将使我们能够跟踪自然发展 以评估这些个体克隆在疾病过程中的频率和分化。使用这些 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 这与每个年龄段的有利结果相关，为疫苗设计提供了信息。年发病率的增加 自身免疫综合征，如在儿科患者中报告的川崎病，表明SARS- CoV-2可能会诱导自身免疫；相反，患有自身免疫综合征的患者可能更容易患上 免疫失调引起的严重疾病。在目标3中，我们将探索这两种可能性。具体来说，我们将 回顾确定自身免疫是否使患者易患严重疾病，以及自身免疫患者是否 对SARS-CoV-2抗原有更多的炎性T细胞反应。我们还将评估自身抗原是否 与SARS-CoV-2序列高度相似的多肽在新冠肺炎中激活更高频率的T细胞 患者和未感染的对照组，我们将确定新冠肺炎患者是否会产生自身抗体。这些 研究将确定每个年龄段的疾病严重程度的特定免疫相关因素，以将患者分成风险组， 告知疫苗设计，并测试自身免疫和新冠肺炎之间的链接，以获得知情的临床护理。