Impact of early microbial exposure on immune ontogeny

早期微生物暴露对免疫个体发育的影响

基本信息

批准号：
10387514
负责人：
Miles Philip Davenport
金额：
$ 39.23万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-24 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387514
关键词：
Address Adult Age Architecture Asthma B-Lymphocytes Barker Hypothesis CD8-Positive T-Lymphocytes Cell Compartmentation Cell Survival Cells Communicable Diseases Data Development Disease Effector Cell Environment Exhibits Exposure to Gene Expression Genomic approach Goals Growth Health Status Heterogeneity Hypersensitivity Immune Immune System Diseases Immune system Individual Infant Infection Inflammatory Bowel Diseases Insulin-Dependent Diabetes Mellitus Knowledge Life Link Maternal-Fetal Exchange Mediating Memory Modeling Mothers Mus Peripheral Positioning Attribute Predisposition Preventive Resistance Risk Role Shapes Specificity Survival Rate T cell response T-Cell Development T-Cell Receptor T-Lymphocyte T-cell receptor repertoire Therapeutic cell behavior disorder risk fetal germ free condition in utero insight mathematical methods mathematical model microbial microbial colonization microbiota mouse model neonate novel offspring pathogen programs single-cell RNA sequencing tool transcriptome sequencing γδ T cells

项目摘要

Project Summary / Abstract Evidence has shown that microbial exposure during critical stages of development can have long-lasting effects on the health status of an individual. However, there is currently no conceptual framework to explain how maternal microbial exposure shapes the fetal and adult immune systems. To fill this knowledge gap, we have developed a novel pet-shop mouse model and compared the ontogeny of CD8+ T cells in mice that were born from either ‘clean’ (SPF) or ‘dirty’ (pet-shop) mothers. Interestingly, the mice raised in the dirty environment mounted a more robust CD8+ T cell response and were highly resistant to infection. To understand how the ontogeny of the CD8+ T cell compartment was altered in the dirty mice, we used fate-mapping ‘timestamp’ mice and found a higher proportion of fast-acting fetal derived CD8+ T cells and fewer slow-acting adult derived CD8+ T cells present in the dirty mice. We also found that immune susceptibility could be normalized between clean and dirty mice by depleting the fetal layer of CD8+ T cells. These data indicate that maternal microbial exposure leads to an accumulation of fetal-derived CD8+ T cells that protects the host against intracellular pathogens. However, the underlying mechanisms remain undefined. Our hypothesis is that maternal microbial exposure alters developmental layering in the offspring by changing the dynamics of cell survival and peripheral selection of T cell receptors. In the first aim, we will combine our fate mapping approach with mathematical modeling to understand how maternal microbial exposure leads to an accumulation of fetal-derived CD8+ T cells. In the second aim, we will use paired single cell TCR/RNAseq to understand how the maternal microbial environments alters the TCR repertoire and immune defense. Knowledge gained from these studies is expected to provide a new conceptual model for understanding how maternal microbial colonization in early life can permanently program the offspring’s immune system and life-long disease risk.

项目摘要 /摘要有证据表明，在发育的关键阶段，微生物暴露会产生长期影响关于个人的健康状况。但是，目前尚无概念框架来解释如何母体微生物暴露塑造胎儿和成人免疫系统。为了填补这个知识差距，我们有开发了一种新型的宠物店小鼠模型，并比较了出生的小鼠CD8+ T细胞的个体发育来自“干净”（SPF）或“肮脏”（宠物商店）母亲。有趣的是，在肮脏的环境中饲养的小鼠安装了更强大的CD8+ T细胞反应，对感染具有高度抗性。了解如何 CD8+ T细胞室的个体发育在肮脏的小鼠中改变了，我们使用了命运映射的“时间戳”小鼠并发现较高比例的快速效率胎儿衍生的CD8+ T细胞和较少的慢速成人衍生的CD8+ T细胞存在于脏小鼠中。我们还发现，可以在清洁之间标准化免疫敏感性和脏小鼠通过耗尽CD8+ T细胞的胎儿层。这些数据表明材料微生物暴露导致胎儿衍生的CD8+ T细胞的积累，可保护宿主免受细胞内病原体的影响。但是，基本机制仍然不确定。我们的假设是材料微生物的暴露通过改变细胞存活和周围选择的动力学来改变后代的发展分层 T细胞接收器。在第一个目的中，我们将脂肪映射方法与数学建模相结合了解母体微生物暴露如何导致胎儿衍生的CD8+ T细胞的积累。在第二个目的，我们将使用配对的单细胞TCR/RNASEQ了解母体微生物环境改变TCR曲目和免疫防御。从这些研究中获得的知识预计将提供了解早期生命中的微生物殖民如何永久性的概念模型编程后代的免疫系统和终身疾病风险。