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寄生着数以万亿计的细菌。未能在以下方面建立宽容 狭窄的早期生活窗口会导致晚年免疫介导性疾病的风险增加，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(PTreg)细胞，抑制对共生微生物的免疫反应。PTreg细胞 在断奶时在肠道中产生；然而，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令人着迷的种群 抗原提呈细胞(APC)，在生命早期丰富在肠道淋巴结内。这些细胞， 被称为Thetis细胞(TCS)的细胞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，我们阐述了一种诱人的可能性，即TCS代表了耐受性APC的专门谱系。我们的目标是 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所起的作用 生活。我们提出的遗传模型允许对TCS进行特定血统的操作，包括Aire的缺失。穿过 这些研究旨在从机制上加深对TC功能的理解。在我们努力定义 对于TCS的生物学，我们试图了解这些细胞的个体发育和发育。使用最先进的 允许我们扰乱肠道微环境的血统追踪方法和遗传模型 以特定于组织和发育阶段的方式，我们将剖析基质和免疫之间的串扰 驱动组织特异性早期免疫发展的细胞。这项提议的首要目标是 建立肠道免疫耐受路线图，描述关键的抗原提呈细胞 对共生抗原的耐受性，以及驱动它们分化的环境线索。这些研究将 I)提供了关于早期生命免疫发育的前所未有的观点，ii)建立了一个新的外周免疫框架 免疫耐受，以及iii)揭示炎症性和免疫介导性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.