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

项目摘要 发育中的婴儿在肠道内定植有数万亿细菌。未能建立公差范围 早期生命窗口狭窄导致晚年免疫介导疾病的风险增加，包括慢性 炎症和癌症。肠耐受产生的核心是幼稚的外周转化， T细胞转化为调节性T细胞（pTreg细胞），抑制对肠道微生物的免疫反应。pTreg细胞 在断奶时在肠中出现;然而，指导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迷人的种群 抗原呈递细胞（APC），在生命早期在肠淋巴结内富集。这些细胞 被称为Thetis细胞（TC），表达自身免疫调节因子Aire，以其在免疫耐受中的关键作用而闻名。 在这里，我们提出了诱人的可能性，TC代表了一个专门的谱系的耐受性APC。我们的目标 揭示它们在指导新生儿pTreg细胞命运中的作用，以及在新生儿中对炎症性疾病的易感性。 生活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。通过 这些研究旨在对TC的功能有一个更深层次的机制理解。在我们努力定义 为了研究TC的生物学，我们试图了解这些细胞的个体发生和发育。使用最先进的 谱系追踪方法和遗传模型，使我们能够扰乱肠道微环境， 组织和发育阶段特异性的方式，我们将剖析基质和免疫之间的串扰， 这些细胞驱动组织特异性的早期免疫发育。本提案的总体目标是 建立肠道免疫耐受的路线图，描述指导免疫耐受的关键抗原呈递细胞， 对大肠杆菌抗原的耐受性，以及驱动其分化的环境线索。这些研究将 i）提供了一个前所未有的早期生命免疫发展的观点，ii）建立了一个新的外周免疫系统框架， 免疫耐受，和iii）揭示炎性和免疫介导的疾病的潜在治疗靶点。

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.