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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型先天淋巴样细胞感知母体膳食胆固醇形成粘膜淋巴样细胞