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.

项目摘要发育中的婴儿在肠内被数万亿个细菌定植。未能在内部建立宽容一个狭窄的早期生活窗口会导致后来生活的免疫介导疾病的风险增加，包括慢性炎症和癌症。肠道耐受性产生的核心是幼稚的外围转换 T细胞进入调节性T（PTREG）细胞，可抑制对共生微生物的免疫回应。 ptreg细胞断奶时出现在肠道中；但是，指示PTREG细胞命运的细胞类型尚不清楚，限制了我们调节PTREG细胞以获得治疗益处的能力。我们最近发现了一个有趣的人口抗原呈递细胞（APC），在早期生命中富含肠道淋巴结。这些细胞，被称为硫醇细胞（TCS），表达自身免疫调节剂AIRE，以其在免疫耐受性中的关键作用而闻名。在这里，我们提出了TCSS代表耐受性APC的专用谱系的诱人可能性。我们的目标揭示其在指导新生儿的PTREG细胞命运方面的作用，以及后来对炎性疾病的敏感性生活。我们提出的遗传模型允许对TC的谱系特异性操纵，包括AIRE的缺失。通过这些研究旨在对TC功能有深刻的机械理解。为了定义 TC的生物学，我们试图了解这些细胞的个体发育和发展。使用最新的谱系追踪方法和遗传模型，使我们能够在肠道中扰动肠道微环境组织和发育阶段特异性的方式，我们将剖析基质和免疫之间的串扰驱动组织特异性早期生命免疫发育的细胞。该提议的总体目标是建立肠道免疫耐受性的路线图对共生抗原的耐受性以及推动其分化的环境提示。这些研究会 i）提供早期生命免疫发展的前所未有的观点，ii）建立一个新的外围框架免疫耐受性和iii）揭示了炎症和免疫介导的疾病的潜在治疗靶标。