Acceptance of non-self: Decoding intestinal immune tolerance during early life

接受非自我：解码生命早期的肠道免疫耐受

基本信息

批准号：
10677728
负责人：
Chrysothemis Brown
金额：
$ 53.1万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
2022-08-05 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10677728
关键词：
ATAC-seq Ablation Acute Address Adult Antigen Presentation Antigen-Presenting Cells Antigens Autoimmune Bacteria Bar Codes Biology CRISPR/Cas technology Cell Differentiation process Cell Maintenance Cell physiology Cells Chronic Citrobacter Colitis Collaborations Computer Analysis Cues Dedications Dendritic Cells Development Disease Elderly Engineering Failure Generations Genetic Genetic Models Goals Growth Health Heterogeneity Immune Immune System Diseases Immune Tolerance Immune response Immune system Infant Infection Inflammation Inflammatory Intestines Life Listeria Malignant Neoplasms Maps Mediating Molecular Mus Neonatal Pathway interactions Peptides Peripheral Phenotype Population Postdoctoral Fellow Predisposition Pregnancy Progesterone Regulation Regulatory T-Lymphocyte Reporter Research Research Personnel Risk Role Signal Transduction T cell differentiation T-Lymphocyte TNFSF11 gene Therapeutic Thymic epithelial cell Thymus Gland Time Tissues Weaning cell type commensal microbes dietary fascinate in utero in vivo lymph nodes mouse model multiple omics neonate novel pathogenic microbe peripheral tolerance postnatal period programs single-cell RNA sequencing stem cells therapeutic target uptake

项目摘要

Project Summary Developing infants are colonized with trillions of bacteria within the intestine. Failure to establish tolerance within a narrow early life window leads to increased risk of immune mediated diseases in later life, including chronic inflammation and cancer. Central to the generation of intestinal tolerance is the peripheral conversion of naïve T cells into regulatory T (pTreg) cells that suppress immune responses to commensal microbes. pTreg cells arise in the intestine at the time of weaning; however, the cell types that instruct pTreg cell fate are not known, limiting our ability to modulate pTreg cells for therapeutic benefit. We recently discovered a fascinating population of antigen presenting cells (APC), enriched within the intestinal lymph nodes during early life. These cells, dubbed Thetis cells (TCs), express the autoimmune regulator Aire, known for its critical role in immune tolerance. Here we set forth the tantalizing possibility that TCs represent a dedicated lineage of tolerogenic APCs. We aim to uncover their role in instructing pTreg cell fate in neonates, and susceptibility to inflammatory disease in later life. Our proposed genetic models allow lineage-specific manipulation of TCs, including deletion of Aire. Through these studies we aim to develop a deep mechanistic understanding of TC function. In our efforts to define the biology of TCs, we seek to understand the ontogeny and development of these cells. Using state-of-the-art lineage tracing approaches and genetic models that allow us to perturb the intestinal micro-environment in a tissue- and developmental-stage-specific manner, we will dissect the cross-talk between stromal and immune cells that drives tissue-specific early life immune development. The overarching goal of this proposal is to establish a roadmap for intestinal immune tolerance, delineating the critical antigen presenting cells that direct tolerance to commensal antigens, and the environmental cues that drive their differentiation. These studies will i) provide an unprecedented view of early life immune development, ii) establish a new framework for peripheral immune tolerance, and iii) reveal potential therapeutic targets for inflammatory and immune mediated diseases.

项目概要发育中的婴儿肠道内定植有数万亿细菌，无法在肠道内建立耐受性。狭窄的早期生命窗口会导致晚年患免疫介导疾病的风险增加，包括慢性病炎症和癌症的产生的核心是幼稚的外周转化。 T 细胞转变为调节性 T (pTreg) 细胞，抑制共生微生物的免疫反应。断奶时肠道中出现；然而，指导 pTreg 细胞命运的细胞类型尚不清楚，我们最近发现了一个令人着迷的群体，限制了我们调节 pTreg 细胞的能力。抗原呈递细胞（APC），在生命早期富集在肠道淋巴结中，被称为 Thetis 细胞 (TC) 的细胞表达自身免疫调节因子 Aire，因其在免疫耐受中的关键作用而闻名。在这里，我们提出了一种诱人的可能性，即 TC 代表了我们的目标是耐受性 APC 的专用谱系。揭示它们在指导新生儿 pTreg 细胞命运以及以后对炎症性疾病的易感性中的作用我们提出的遗传模型允许对 TC 进行谱系特异性操作，包括删除 Aire。这些研究的目的是加深对 TC 功能的机制理解。 TC 的生物学，我们寻求利用最先进的技术来了解这些细胞的个体发育和发育。谱系追踪方法和遗传模型使我们能够扰乱肠道微环境组织和发育阶段特定的方式，我们将剖析基质和免疫之间的串扰该提案的总体目标是驱动组织特异性早期生命免疫发育。建立肠道免疫耐受的路线图，描绘指导的关键抗原呈递细胞对共生抗原的耐受性以及驱动其分化的环境因素。 i) 提供生命早期免疫发展的前所未有的观点，ii) 建立外周免疫发展的新框架免疫耐受，以及iii)揭示炎症和免疫介导疾病的潜在治疗靶点。