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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