Exploring the thymic origin of group 2 innate lymphoid cells

探索第 2 组先天淋巴细胞的胸腺起源

基本信息

批准号：
10472249
负责人：
Xiao-Hong Sun
金额：
$ 61.8万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472249
关键词：
Address Adoptive Transfer Adult Behavior monitoring Biological Blood Blood Cells Blood Circulation Bone Marrow CD8B1 gene Cell Differentiation process Cells Child Common Lymphoid Progenitor Complex Data E protein Elderly Embryonic Development Environment Flow Cytometry Frequencies Gene Expression Genetic Transcription Growth Helminths Human Immune Immune response Immunity In Vitro Infection Instinct Investigation Knowledge Laboratories Learning Light Lung Lymphoid Cell Maintenance Molecular Monitor Mouse Strains Multipotent Stem Cells Mus Natural Immunity Newborn Infant Nude Mice Only Child Output Papain Peripheral Play Population Population Heterogeneity Production Protein Deficiency Reporter Reporting Role SARS-CoV-2 infection Shapes Signal Induction Signal Transduction Small Intestines Source Stains Stimulus T-Cell Receptor Genes T-Lymphocyte Testing Thymus Gland Tissues Transcription Repressor Up-Regulation Wild Type Mouse Work adaptive immunity base behavioral study cell behavior clinically relevant clinically significant cytokine follow-up genetic signature immunoreaction in vivo mouse development notch protein prepuberty progenitor reconstitution response single-cell RNA sequencing transcription factor transcriptome transcriptome sequencing young adult

项目摘要

Abstract Innate lymphoid cells (ILCs) play diverse roles in shaping innate and adaptive immunity. These cells exist as heterogeneous populations and their identities are influenced by their tissue environments. Likewise, the ontogeny of ILCs is also complex. Although ILCs are thought to arise from bone marrow progenitors or tissue resident progenitors distributed during embryogenesis, work from our laboratory strongly suggest that ILCs at least ILC2s can also be generated in the thymus, not only from multipotent progenitors but also from committed T cell precursors. Our recent data using single cell RNA sequencing suggest that a substantial fraction of the ILC-enriched population in the blood of wild type mice (WT) come from the thymus, and their equivalents can also be found in peripheral tissues. We thus hypothesize that the thymus exports a substantial amount of ILC precursors to the circulation, which may replenish ILC2s and/or other ILCs in peripheral tissues in steady-state or upon immune challenges and the thymus-derived ILCs may have distinct functions. In this renewal proposal, we intend to follow up on these new exciting findings and determine the function of these thymus-derived ILC precursors and their biological significant. We will further characterize thymus-derived ILC-precursors in the lung and small intestine and determine their frequencies during mouse development. We will also identify thymus-derived ILC precursors in human blood, thus gaining appreciation of the clinical relevance of these cells. We will then focus on learning the function of these thymus-derived ILC precursors using in vitro and in vivo approaches, as well as adoptive transfer of purified ILC precursors into Rag2-/-Il2g-/- mice which are devoid of ILCs. The behaviors of these cells in type 2 immune reactions will be monitored. Finally, we will assess the cell-intrinsic functional differences among WT ILC2s generated from bone marrow common lymphoid progenitors (CLP) and thymic DN1 and DN3 T cell precursors. Taken together, studies outlined in this proposal will further our understanding of thymus-derived ILCs, which will help establish a new paradigm regarding to the production and maintenance of ILC pools. Because the presence of an active thymus represents one of the major differences between children and adults, knowledge about thymus-derived ILCs may shed light on their different immune responses such as those during Covid-19 infection.

抽象的先天淋巴样细胞（ILC）在塑造先天和适应性免疫方面发挥了各种作用。这些细胞存在为异质种群及其身份受组织环境的影响。同样， ILC的个体发育也很复杂。尽管认为ILC是由骨髓祖细胞或组织引起的在胚胎发生过程中分布的居民祖细胞，我们实验室的工作强烈表明ILC在最少的ILC2也可以在胸腺中生成定制的T细胞前体。我们使用单细胞RNA测序的最新数据表明野生型小鼠（WT）血液中富含ILC的人群的一部分来自胸腺，它们在外周组织中也可以找到等效物。因此，我们假设胸腺出口A 循环的大量ILC前体可以补充ILC2和/或其他ILC 在稳态或免疫挑战的外周组织中，胸腺来源的ILC可能具有不同的功能。在此续签建议中，我们打算跟进这些新的令人兴奋的发现和确定这些胸腺衍生的ILC前体及其生物学意义的功能。我们将进一步表征肺和小肠中的胸腺衍生的ILC替代者，并确定其频率在小鼠发育过程中。我们还将确定人类血液中胸腺衍生的ILC前体，从而获得对这些细胞的临床相关性的欣赏。然后，我们将专注于学习这些功能胸腺来源的ILC前体使用体外和体内方法，以及纯化的收养转移 ILC前体进入RAG2 - / - IL2G - / - 没有ILC的小鼠。这些细胞在2型免疫中的行为反应将受到监控。最后，我们将评估WT ILC2之间的细胞内部功能差异由骨髓普通淋巴样祖细胞（CLP）以及胸腺DN1和DN3 T细胞前体产生。综上所述，该提案中概述的研究将进一步了解胸腺来源的ILC，这是我们的理解将有助于建立有关ILC池的生产和维护的新范式。因为活性胸腺的存在代表儿童和成人之间的主要差异之一，知识关于胸腺衍生的ILC可能会揭示其不同的免疫反应，例如Covid-19期间的免疫反应感染。