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.

项目摘要怀孕期间的某些感染与发育和行为异常有关后代。母亲的明显炎症反应是否会对后代免疫系统的发展尚不清楚。知识的差距直接与缺乏对胎儿通常如何发展淋巴细胞如何发展的详细见解有关的。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活跃的区域研究有许多未解决的基本问题。特别是，未知是否免疫系统是a）一维干细胞或b）多层，每一层由功能专业的单元系统制成量身定制为动物的独特发育年龄。我们发现皮肤淋巴细胞（免疫哨兵）防止皮炎起源于祖细胞至关重要仅在胚胎中发展的基因程序。重要的是，数据进一步表明独特免疫哨兵的遗传网络在出现之前在胎儿组织中活跃胎儿肝脏中的造血干细胞（HSC）。已经假定胎儿HSC是所有淋巴细胞的原代干细胞。因此，我们的结果表明未发现的存在胚胎先天淋巴样祖细胞（EILP）不同于经典HSC或其即时子细胞朝向淋巴样谱系。我们计划识别和表征EILP 亚型通过采用一系列分子信标，每种都包含在基因组中，报告预测的EILP的基因网络中心的活性。胎儿中的稀有细胞将捕获信标的指定组合，并将分析这些候选EILP 分子在单个细胞水平上并移植到动物中以确定其生成潜在的。预计候选EILP会优先生成粘膜免疫前哨胎儿和新生动物，一旦使这些哨兵长期存在，成年。这些先天前哨的缺失或改变会导致组织异常的异常平衡和炎症性疾病。一旦建造了胚胎造血谱系树怀孕的免疫扰动会影响先天淋巴细胞的发展系统评估。