Uncovering the hidden universe of metabolite-specific T lymphocytes,using human multiorgan microphysiological systems.

项目摘要 代谢和炎症性疾病，如自身免疫性和神经退行性疾病， 令人震惊的速度。其中许多不是组织特异性发生，而是复杂且经常重叠的病理 无法治愈的未知原因例子包括肠-肝轴的并发病理，例如 炎症性肠病和肝脏的炎症性病理。“非常规”T的发现 淋巴细胞及其对非肽抗原的反应能力，标志着探索如何在一个新的领域， 迁移细胞和免疫代谢网络形成自身免疫和代谢疾病的出现。 这些由异质性淋巴细胞群组成，如粘膜相关的不变T细胞， 其不变TCR可以通过MHC样抗原呈递来识别细胞和微生物代谢产物， 受体1（MR 1）。新出现的证据表明，MR 1限制性T细胞参与了各种各样的免疫反应。 从溃疡性结肠炎到1型糖尿病、自身免疫性肝炎和多发性硬化症， 具体和非具体的方法。 然而，缺乏与人类生理学相关的模型是我们理解人类生理学的一个重大障碍。 MR 1限制性T细胞如何影响宿主和疾病。我们开发了一种方法， 供体匹配组织的人类微生理学模型（MOMPS）和无偏见的系统生物学工具， 深入了解细胞串扰和免疫代谢疾病之间的因果关系。为了 为了获得关于MR 1限制性淋巴细胞的异质性和功能性的关键知识，我们将 联合收割机对供体匹配组织中人MR 1限制性T细胞的单细胞表征， 循环，在肠道-肝脏轴的微生理学模型中进行机制研究。这些MOMPS将是 用于系统地搜索MR 1限制性淋巴细胞、组织和 外部因素通过重建供体组织在各种复杂程度。每个级别都将受到挑战， 预先确定的炎症和代谢紊乱。基于相互作用的变化的多组学观察 在每一个复杂度的扰动将使我们能够构建相互作用网络，揭示因果关系， 实体之间的关系。通过计算工具和对细胞的分子基础的解析， 和组织内稳态，MOMPS代表了一个独特的机会，系统地剖析如何相互作用， 较低的顺序在器官系统内部和之间的宏观尺度上通知新的行为。而肠肝轴 将作为一个模型，在这一建议，发达国家的做法，连同基本的生物学见解， 实质组织的MR 1表达和MR 1限制性T细胞的功能，将适用于其他器官 系统和各种病理。我们的首要目标是确定切实的目标和新的基于细胞的 调节自身免疫性病理的方法，而且还提供了新的工具， 复杂疾病的基本起源

PROJECT SUMMARY Metabolic and inflammatory disorders such as autoimmune and neurodegenerative diseases are increasing at alarming rates. Many of these are not tissue-specific occurrences but complex and often overlapping pathologies of unknown origin for which no cure exists. Examples are concurring pathologies of the gut-liver axis, such as inflammatory bowel disease and inflammatory pathologies of the liver. The discovery of “unconventional” T lymphocytes and their ability to respond to non-peptide antigens, marks a new area in the exploration of how migratory cells and immunometabolic networks shape the emergence of autoimmune and metabolic diseases. These are comprised of a heterogeneous group of lymphocytes, such as mucosa-associated invariant T cells, whose invariant TCR can recognize cellular and microbial metabolites via presentation through the MHC-like receptor 1 (MR1). Emerging evidence suggest MR1-restricted T cells to be implicated in a wide variety of disorders ranging from ulcerative colitis to type 1 diabetes, autoimmune hepatitis and multiple sclerosis via TCR- specific and non-specific means. However, lack of models relevant to human physiology represents a significant hurdle in our understanding of how MR1-restricted T cells affect the host and diseases. We have developed an approach that utilizes multiorgan human microphysiological models (MOMPS) of donor-matched tissues and unbiased systems biology tools to gain granular insight into causal relationships between cellular crosstalk and immunometabolic illnesses. In order to gain critical knowledge about the heterogeneity and functionality of MR1-restricted lymphocytes, we will combine single-cell characterization of human MR1-restricted T cells across donor-matched tissues and circulation, with mechanistic studies in a microphysiological model of the gut-liver axis. These MOMPS will be used to systematically search for causal relationships between MR1-restricted lymphocytes, tissues, and external factors by reconstructing donor tissue at various levels of complexity. Each level will be challenged via predetermined inflammatory and metabolic perturbations. Multiomic observation of changes based on interaction and perturbation at each degree of complexity will allow us to construct interaction networks that reveal causal relationships among entities. With computational tools and resolution into molecular underpinnings of cellular and tissue homeostasis, MOMPS represent a unique opportunity to systematically dissect how interactions at a lower order inform new behavior at the macro scale within and between organ systems. While the gut-liver axis will serve as a model in this proposal, the developed approach, together with fundamental biological insights into MR1 expression by parenchymal tissue and function of MR1-restricted T cells, will be applicable to other organ systems and a variety of pathologies. Our overarching goal is to identify tangible targets and new cell-based approaches to modulate autoimmune pathologies but also contribute new tools that shed light on the fundamental origins of complex diseases