Identification and single cell analysis of embryonic lymphoid progenitors that generate neonatal innate T cells

产生新生儿先天 T 细胞的胚胎淋巴祖细胞的鉴定和单细胞分析

基本信息

批准号：
10159863
负责人：
Joonsoo Kang
金额：
$ 49.68万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-12 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159863
关键词：
Adaptive Immune System Adult Affect Age Animals Antigen Receptors Area Atopic Dermatitis Awareness Behavioral Biological Assay Birth Blood Cells Bone Marrow Cell Transplantation Bone Marrow Cells Breast Feeding Cell Lineage Cells Child Health Choristoma Data Dermal Dermatitis Development Developmental Delay Disorders Developmental Process Dimensions Disease Embryo Embryonic Development Endothelial Cells Environment Exhibits Family Fetal Development Fetal Liver Fetal Tissues Fetus Future Generations Genes Genetic Genome Health Hematopoiesis Hematopoietic Hematopoietic stem cells Heterogeneity Homeostasis Human Immune Immune System Diseases Immune response Immune system Immunity Immunologics Infection Infectious Agent Inflammation Inflammatory Inflammatory Response Interleukin-17 Intervention Knowledge Label Life Link Lymphocyte Lymphocyte Function Lymphoid Lymphoid Cell Lymphopoiesis Maps Mediating Mediator of activation protein Metabolic Modality Molecular Molecular Analysis Mothers Mucous Membrane Mus Mutation Neonatal Newborn Animals Newborn Infant Normal tissue morphology Paraaortic Pathway interactions Patients Physiologic pulse Placenta Play Pregnancy Premature Labor Process Property Radiation Reporting Research Resolution Risk Role SOX13 gene Sentinel Shapes Signal Transduction Site Skin Specific qualifier value Symptoms System Systems Development T-Lymphocyte T-Lymphocyte Subsets Testing Thymus Gland Time Tissues Transplantation Trees Vaccination Yolk Cell Yolk Sac aged base cell type chemotherapy cytokine daughter cell design embryo tissue fetal fetus cell fitness hematopoietic tissue hemogenic endothelium immune activation improved in utero insight liver transplantation mature animal microbiome neonate nutrition offspring pathogen patient-level barriers post-transplant postnatal premature prevent progenitor programs response single cell analysis stem cells transcription factor transcriptomics γδ T cells

项目摘要

Project Summary Certain infections during pregnancy are linked to developmental and behavioral abnormalities in the offspring. Whether overt inflammatory responses in the mother can have a lasting impact on the development of immune system of the offspring is unknown. This gap in knowledge is directly linked to a lack of detailed insights into how lymphocytes normally develop in the fetus. How animals generate multiple immunocyte subtypes from fetal to aged stages remains an active area of research with many unresolved fundamental questions. In particular, it is unknown whether the immune system is a) one dimensional, a collective of diverse cell types generated from a single stem cell or is b) multi-layered, with each layer made of functionally specialized cell systems tailored to the distinct developmental age of an animal. We discovered that skin lymphocytes (immune sentinels) essential to prevent dermatitis originate from progenitors with dedicated gene programs that only develop in embryos. Importantly, data further suggest that the unique genetic networks of immune sentinels are active in fetal tissues prior to the emergence of a single hematopoietic stem cell (HSC) in the fetal liver. It has been assumed that fetal HSCs are the primary stem cell for all lymphocytes. Our results thus suggest the existence of undiscovered embryonic innate lymphoid progenitors (eILPs) distinct from classical HSCs or their immediate daughter cells primed toward the lymphoid lineage. We plan to identify and characterize eILP subtypes by employing a spectrum of molecular beacons, each embedded in the genome and reporting the activity of predicted gene network hubs of eILPs. Rare cells in the fetus with a specified combination of beacons will be captured and these candidate eILPs will be analyzed molecularly at a single cell level and transplanted into animals to determine their generative potential. Candidate eILPs are predicted to preferentially generate mucosal immune sentinels in fetal and neonatal animals, and once these sentinels are made they persist long term, well into adulthood. Absence or alterations of these innate sentinels results in aberrant tissue homeostasis and inflammatory disorders. Once the embryonic hematopoietic lineage tree is constructed how immune perturbations in pregnancy impact the development of innate lymphocytes can be systematically assessed.

项目概要怀孕期间的某些感染与发育和行为异常有关后代。母亲体内明显的炎症反应是否会对胎儿产生持久影响后代免疫系统的发育尚不清楚。这种知识上的差距直接这与缺乏对胎儿淋巴细胞正常发育的详细了解有关。如何动物从胎儿到老年阶段产生多种免疫细胞亚型仍然是一个活跃领域的研究有许多未解决的基本问题。特别是，尚不清楚是否免疫系统是a）一维的，由单一细胞产生的不同细胞类型的集合干细胞或 b) 多层，每一层均由功能专门的细胞系统组成根据动物的不同发育年龄量身定制。我们发现皮肤淋巴细胞（免疫哨兵）对于防止皮炎起源于具有专门功能的祖细胞至关重要仅在胚胎中发育的基因程序。重要的是，数据进一步表明，独特的免疫哨兵的遗传网络在单个个体出现之前就在胎儿组织中活跃。胎儿肝脏中的造血干细胞（HSC）。据认为，胎儿 HSC 是所有淋巴细胞的初级干细胞。因此，我们的结果表明存在未被发现的胚胎先天淋巴祖细胞 (eILP) 与经典 HSC 或其直接细胞不同子细胞已准备好进入淋巴谱系。我们计划识别和描述 eILP 通过使用一系列分子信标来识别亚型，每个分子信标都嵌入基因组中，报告 eILP 的预测基因网络中心的活动。胎儿中的稀有细胞将捕获指定的信标组合并分析这些候选 eILP 在单细胞水平上进行分子研究并移植到动物体内以确定其生殖能力潜在的。候选 eILP 预计将优先产生粘膜免疫哨兵胎儿和新生动物，一旦这些哨兵被制造出来，它们就会长期存在，并进入成年期。这些先天哨兵的缺失或改变会导致组织稳态异常和炎症性疾病。一旦胚胎造血谱系树构建完毕，如何怀孕期间的免疫扰动会影响先天淋巴细胞的发育系统地评估。