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Unraveling Human T Follicular Helper Cell Development

揭开人类滤泡辅助 T 细胞发育的谜团

基本信息

批准号：
10568500
负责人：
Philip A Mudd
金额：
$ 58.12万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-06 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10568500
关键词：
2019-nCoV Activities of Daily Living Address Adoptive Transfer Affinity Animal Model Antibodies Antibody Affinity Antigens Autologous Axillary lymph node group B-Cell Development B-Lymphocytes Biological Assay Biological Models Blood CD4 Positive T Lymphocytes COVID-19 COVID-19 pandemic COVID-19 vaccine Cell Maturation Cell Separation Cell physiology Clinical Collaborations Communicable Diseases Data Data Set Development Epitopes Event Exhibits Fine needle aspiration biopsy Flow Cytometry Genetic Transcription Helper-Inducer T-Lymphocyte Human Human Volunteers Immune response Immunoglobulin Class Switching Immunologist Infection Influenza vaccination Intramuscular Knowledge Lead Maintenance Measures Memory Memory B-Lymphocyte Methods Modeling Mus Participant Phenotype Plasma Cells Play Population Process Production Productivity Proteins RNA vaccination RNA vaccine Reaction Role SARS-CoV-2 spike protein Sampling Series Signal Transduction Site Sorting Specificity Structure of germinal center of lymph node Supporting Cell Surface System T cell receptor repertoire sequencing T-Cell Receptor T-Lymphocyte Subsets Techniques Testing Time Tissues Tonsillectomy Utah Vaccination Vaccines Variant Work antigen challenge cohort cytokine deltoid muscle draining lymph node gene function high dimensionality human model in vivo lipid nanoparticle lymph nodes mouse model neutralizing antibody novel plasma cell development recruit response seasonal influenza secondary lymphoid organ single-cell RNA sequencing time interval ultrasound vaccine distribution vaccine platform

项目摘要

ABSTRACT Neutralizing antibodies are critical for protection from infectious diseases. The lymph node (LN) germinal center (GC) is the site where B cells undergo antibody affinity maturation and develop into long-lived plasma cells – key events that are required for the development of highly effective neutralizing antibodies following infection or vaccination. T follicular helper cells (TFH) are the CD4+ T cell subset responsible for providing B cell help during an ongoing GC. TFH are absolutely required for GC formation and maintenance. By extension, TFH are necessary to produce effective neutralizing antibodies following antigen exposure. While many aspects of the TFH response and TFH function have been examined in animal models, human TFH responses in the draining LN have only recently been explored with the novel application of an established technique: serial ultrasound-guided fine needle aspiration of draining LN following vaccination. With this technique, we recently demonstrated that the antigen-specific TFH response to SARS-CoV-2 spike (S) protein mRNA vaccination persists in the GC for more than 4 months following vaccination and correlates with the presence of S-specific GC B cells. Furthermore, we have noted substantial LN TFH transcriptional phenotypic changes suggestive of functional maturation over this prolonged GC time interval using single cell RNA-seq in a small preliminary cohort. In this proposal, we will expand upon these findings to address our primary hypothesis: human TFH phenotypic maturation occurs over time in the draining LN following vaccination and these phenotypic changes are associated with changes in TFH function. To explore this hypothesis, we propose three specific aims: 1) We will first establish that TFH phenotypic maturation occurs over time in multiple antigen-specific TFH populations that we will define and characterize from a cohort of fourteen COVID-19 mRNA vaccine recipients using single cell RNA-seq and ex vivo epitope identification methods. 2) We will determine how these antigen-specific TFH populations change in a tertiary immune response following COVID-19 mRNA vaccine “boost” and continued serial LN sampling of the same cohort participants. We will also ascertain if new antigen-specific TFH populations are recruited to the GC during a recall response. 3) Finally, we will verify that the profound phenotypic changes we observe lead to changes in the functional capacity of antigen-specific TFH to provide help to B cells using an ex vivo system of sorted human LN TFH and an in vivo murine adoptive transfer model. By addressing these aims, we will significantly enhance our understanding of the role that human TFH play in directing GC B cell responses to vaccination.

摘要