Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to shape mucosal lymphoid organ development

胚胎 3 型先天淋巴细胞感知母体饮食胆固醇以塑造粘膜淋巴器官发育

基本信息

批准号：
10632055
负责人：
Andrea Reboldi
金额：
$ 20.94万
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：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10632055
关键词：
25-hydroxycholesterol Adult Anatomy Birth CCR6 gene CRISPR/Cas technology Cell Maturation Cells Cholesterol Cholesterol Homeostasis Chronic Cues Data Development Dietary Cholesterol Dietary Component Differentiation Inducer Duodenum Embryo Endowment Environment Enzymes Evolution Exposure to Fetal Development Fetal Liver Fetus Future G-Protein-Coupled Receptors Generations Genes Genetic Transcription Helper-Inducer T-Lymphocyte Homeostasis Image Immune Immune response Immune system Immunity Impairment In Vitro Infection Intake Intestines Knockout Mice Life Ligands Link Location Lymphocyte Lymphoid Lymphoid Cell Lymphoid Tissue Malnutrition Maps Maternal Health Mediating Mesentery Metabolic Mixed Function Oxygenases Molecular Mothers Mucous Membrane Mus Mutation Nature Neonatal Newborn Infant Organ Organogenesis Persons Peyer&apos s Patches Positioning Attribute Pregnancy Process Production Proteins Reaction Regulation Reporter Reporting Role Shapes Side Signal Transduction Small Intestines Spleen Sterols Stromal Cells Systemic infection Testing Thymus Gland Tissues Uterus adaptive immune response cell type chemokine receptor cholesterol biosynthesis commensal bacteria conditional knockout cytokine design dietary enteric pathogen fetal fetus cell high reward high risk imprint in utero in utero transplantation in vivo insight lymph nodes lymphoid organ lymphoid structures mother nutrition neonate novel oral vaccine organ growth postnatal programs response scaffold secondary lymphoid organ sensor two-photon

项目摘要

Embryonic type 3 innate lymphoid cells sense maternal dietary cholesterol to shape mucosal lymphoid organ development Summary During pregnancy, the fetal immune system develops in the uterine environment and relies on developmental programs to initiate the organogenesis of secondary lymphoid organs, including spleen and lymph node. This evolutionary conserved process endows the fetus with the ability to orchestrate the immune response after birth and to react to the triggers present in the environment. Lymphoid tissue inducer (LTi) cells are fetal innate lymphocytes that develop during intrauterine life and are deputed to coordinate the development of secondary lymphoid organs. People with mutations in genes controlling LTi have impaired lymph node formation and are predisposed towards mucocutaneus and systemic infection. While it is established that LTi function is critical to prepare the neonate with a functional scaffold to mount immune response, the mechanisms controlling anatomically distinct intestinal secondary organs organogenesis are unclear. We discovered that LTi that form intestinal the Peyer’s patches, gut-specific secondary lymphoid organs, require the coordinated action of two migratory G protein coupled receptor (GPCR) GPR183 (EBI2) and the chemokine receptor CCR6. However, the nature of the intestinal anatomical location attracting Peyer’s patches LTi and its effect on LTi differentiation is unknown. In this project we will test the hypothesis that intestinal LTi cells position themself in proximity of a differentiating “metabolic niche”: maternal diet provides the maturation cues, which is a cholesterol byproduct generated in the neonatal gut by resident stromal cells. This is a high risk and high reward project, designed to establish the critical importance of cholesterol metabolite production and sensing for fetal innate lymphocytes differentiation in the gut. The conceptual basis is unique as there are no precedents for the integration of GPCR- dependent maturation and metabolic switch in tissue resident innate lymphocytes during development. Moreover, no metabolic regulation intimately linked to maternal diet and mediated by fetal stromal cells that exploit same cues that will be generated during tissual adult function have been reported. This lack of precedent makes the project risky, but if proven to be accurate will fundamentally alter our understanding of mucosal innate lymphocytes sensing of environmental alterations and expand the functional domains of cholesterol and its byproducts in building and maintaining a healthy immune system, especially in newborns.

胚胎 3 型先天淋巴细胞感知母体饮食胆固醇以塑造粘膜淋巴器官发育概括怀孕期间，胎儿的免疫系统在子宫环境中发育，并依赖于发育启动次级淋巴器官（包括脾脏和淋巴结）的器官发生的程序。进化保守过程使胎儿具有在出生后协调免疫反应的能力并对环境中存在的触发因素做出反应。淋巴组织诱导剂 (LTi) 细胞是胎儿先天淋巴细胞，在子宫内发育，负责协调二级淋巴器官的发育。基因突变的人。控制 LTi 的淋巴结形成受损，并且易于皮肤粘膜和全身性虽然已确定 LTi 功能对于为新生儿准备功能性支架至关重要。增强免疫反应，控制解剖学上不同的肠道次要器官的机制器官发生尚不清楚。我们发现，形成肠道派尔氏淋巴结（肠道特异性次级淋巴器官）的 LTi 需要两个迁移性 G 蛋白偶联受体 (GPCR) GPR183 (EBI2) 和趋化因子的协调作用然而，吸引派尔氏淋巴结 LTi 的肠道解剖位置的性质及其对 LTi 分化的影响尚不清楚，在本项目中，我们将测试肠道 LTi 细胞位置的假设。他们自己接近一个差异化的“代谢生态位”：母亲的饮食提供了成熟的线索，这是常驻基质细胞在新生儿肠道中产生的胆固醇副产物。这是一个高风险和高回报的项目，旨在确立胆固醇代谢物的至关重要性肠道中胎儿先天淋巴细胞分化的产生和传感的概念基础是独特的。组织中 GPCR 依赖性成熟和代谢转换的整合尚无先例此外，发育过程中固有的淋巴细胞没有与母体密切相关的代谢调节。饮食并由胎儿基质细胞介导，利用与成人组织功能期间产生的相同线索已被报道。缺乏先例使得该项目存在风险，但如果被证明是准确的，将从根本上改变我们的了解粘膜先天淋巴细胞对环境变化的感知并扩展其功能胆固醇及其副产品在建立和维持健康的免疫系统方面的作用，特别是在新生儿。