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

• 批准号: 10510646
• 负责人: Andrea Reboldi
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 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/10510646
• 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; 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' s Patches; Positioning Attribute; Pregnancy; Process; Production; Proteins; 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

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型固有淋巴样细胞感知母体膳食胆固醇以形成粘膜淋巴样 器官发育 摘要 在怀孕期间，胎儿的免疫系统在子宫环境中发育，并依赖于 启动次级淋巴器官器官发生的方案，包括脾和淋巴结。这 进化保守的过程赋予胎儿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。 淋巴组织诱导物(LTI)细胞是胎儿固有的淋巴细胞，在宫内发育，是 代表协调次级淋巴器官的发育。基因突变的人 控制LTI会损害淋巴结节的形成，并易发生粘液性皮肤病和全身性 感染。虽然已经确定LTI功能对于准备具有功能支架的新生儿是至关重要的，以 挂载免疫反应，控制解剖上不同的肠道次级器官的机制 器官发生尚不清楚。 我们发现，形成肠道Peyer氏斑的LTI，肠道特有的次级淋巴器官，需要 两种迁移性G蛋白偶联受体GPR183(EBI2)与趋化因子的协同作用 受体CCR6。然而，吸引Peyer‘s补片的肠道解剖位置的性质及其对LTI的影响 对LTI分化的影响尚不清楚。在这个项目中，我们将检验肠道LTI细胞位置的假设 处于分化的“新陈代谢生态位”附近：母亲的饮食提供了成熟的线索，这是 一种由常驻基质细胞在新生儿肠道中产生的胆固醇副产品。 这是一个高风险和高回报的项目，旨在确定胆固醇代谢物的关键重要性。 胎儿肠道内固有淋巴细胞分化的产生和感觉。概念基础是唯一的，因为 在组织中整合依赖于GPCR的成熟和代谢开关是没有先例的 发育过程中的居民先天淋巴细胞。此外，没有代谢调节与母体密切相关 饮食，并由胎儿基质细胞调节，这些细胞利用在组织成体功能过程中将产生的相同信号 已经被报道过。 这种缺乏先例的做法使该项目具有风险，但如果被证明是准确的，将从根本上改变我们的 了解粘膜固有淋巴细胞对环境变化的感知并拓展其功能 胆固醇及其副产物在建立和维持健康免疫系统中的作用领域，特别是在 新生儿。