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：
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
项目类别：
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

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.

项目摘要一些共同的19例患者得很好，患有无症状或轻度疾病，而多达20％的患者患有可能致命的严重症状。最近的研究表明，炎症细胞因子升高和降低严重疾病患者的T细胞数量，表明免疫反应的差异可能是基础的疾病结局的差异。但是，受保护与病理免疫反应的特征对SARS- COV-2不太了解。此外，儿童倾向于经历米勒症状，而较早个体更容易受到严重疾病的影响，但尚不清楚这是否是与年龄相关的函数免疫调查的差异。在AIM 1中，我们建议执行成对的单细胞转录组学，蛋白质组学和TCR曲目测序的纵向血液样本来自不同的19例患者年龄和疾病的严重程度是为了全面介绍对SARS-的免疫反应的轨迹 COV-2并确定与疾病严重程度和年龄相关的候选免疫特征。候选人签名将在较大的患者队列中进行测试和完善。当前的疫苗工作重点是引起中和针对SARS-COV-2的抗体。 CD4+ T细胞反应需要激活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率和保持免疫记忆。但是，激活保护性T细胞反应的病毒表位仍然存在未知。在AIM 2中，我们将从用于单细胞分析的纵向患者样品中激活T细胞用重叠肽的“巨型木材”为目标1，跨越单个SARS-COV-2抗原。活化的T细胞将经过单细胞多摩斯分析，使我们能够识别响应的克隆的TCR序列到每个病毒蛋白。对AIM 1的数据集的回顾性分析将使我们能够遵循自然发展这些单独的克隆以评估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子和记忆阶段激活特定的T细胞克隆这与每个年龄段的有利结果相关，并为疫苗设计提供了信息。事件增加了自身免疫性综合征，例如小儿患者报道的川崎样疾病，表明SARS- COV-2可能会诱发自身免疫性；相反，自身免疫性综合征的患者可能更容易受到由于免疫失调引起的严重疾病。在AIM 3中，我们将探索这两种可能性。具体来说，我们会的回顾性确定自身免疫是否使患者患有严重疾病，以及自身免疫性患者对SARS-COV-2抗原具有更多的炎性T细胞反应。我们还将评估是否自动抗原与SARS-COV-2 PETIDE的高序列相似性可激活Covid-19的T细胞的较高频率患者与未感染的对照组，我们将确定COVID-19患者是否患有自身抗体。这些研究将在每个年龄段确定特定的疾病严重性免疫力，以将患者分类为风险组，通知疫苗设计，并在自身免疫和Covid-19之间进行测试联系，以进行知情临床护理。