Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments

离散肠道微环境中 T 细胞功能的核受体控制

• 批准号: 10757138
• 负责人: Mark Scott Sundrud
• 金额: $ 20.62万
• 依托单位: DARTMOUTH-HITCHCOCK CLINIC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757138
• 关键词: Nuclear; Receptor; Control; Cell; Function

Project Summary The gut is a central immunological organ, where host-microbe interactions shape immune tolerance and inflammation, both locally and systemically. Yet prevailing immunological views conflate the two distinct organs that comprise the gut—small and large intestine (or SI and LI)—which impedes more robust understanding of mucosal immune regulation, and misses opportunities to develop safer, more targeted therapies for human inflammatory bowel diseases (IBDs). The premise of this application, founded on recent discoveries from, and synergy between, the two PIs (Sundrud, Weaver), is that mucosal CD4+ T cells use distinct sets of nuclear receptors (NRs) in the SI and LI to interface with divergent classes of host- and microbe-derived metabolites, respectively. Recent work from the Sundrud lab establishes that Foxp3- T effector (Teff) subsets—Th1, Th17 cells—use a NR with no previously known immunological function, the constitutive androstane receptor (CAR/Nr1i3), to direct a ‘hepatocyte-like’ transcriptional response to contend with potentially cytotoxic bile acid (BA) concentrations in the SI. A large gradient of BAs exists between the SI (millimolar) and LI (micromolar) due to ‘enterohepatic’ circulation—primary BAs synthesized in the liver, stored in the gallbladder, and secreted post- prandially into the duodenum are actively reabsorbed by specialized enterocytes in the ileum for portal recirculation to the liver. Because BAs are lipophilic, they can be toxic and pro-inflammatory in enterohepatic tissues; a host of nuclear receptors—including CAR—have evolved to suppress BA toxicity in hepatocytes and enterocytes. Our data suggest that enterohepatic circulation creates a uniquely harsh SI microenvironment to which infiltrating T cells must adapt to maintain tolerance and tissue homeostasis. The LI, by contrast, harbors 103-107 times more bacteria than the SI, and ~1000-fold less BAs. Accordingly, microbes and their metabolites— short chain fatty acids (SCFAs; e.g., butyrate), secondary BAs (produced via microbial metabolism of residual primary BAs)—become central to immune regulation in the LI. SCFAs inhibit histone deacetylase enzymes (HDACs) and stabilize Foxp3 gene expression in peripherally-induced T regulatory cells (iTregs), whereas secondary BAs promote LI Treg maintenance through another NR, vitamin D receptor (VDR). Thus, while antigens from the enteric flora are required for priming both pro- and anti-inflammatory T cell responses throughout the intestinal tract, we hypothesize that marked differences in the abundance of bugs and bile in the SI vs. LI establish consequential metabolite gradients that are sensed by different NRs to instruct compartmentalized T cell regulatory functions. We test this hypothesis through complementary, but not inter- dependent, Aims, leveraging new mouse models, as well as a library of recombinant protein-based NR activity assays, to define the mechanisms governing the transcriptional regulation, biochemical activation, and downstream cellular functions of CAR (in SI Teff cells) and VDR (in LI iTreg cells). Successful completion of these Aims will establish new biological paradigms and inform more precise approaches to treat human IBDs.

项目概要 肠道是一个中心免疫器官，宿主与微生物的相互作用塑造免疫耐受和 局部和全身炎症。然而，流行的免疫学观点将这两个不同的器官混为一谈 组成肠道的小肠和大肠（或 SI 和 LI）——这阻碍了对 粘膜免疫调节，并错过了为人类开发更安全、更有针对性的疗法的机会 炎症性肠病（IBD）。该应用程序的前提是基于最近的发现，并且 两个 PI（Sundrud、Weaver）之间的协同作用是粘膜 CD4+ T 细胞使用不同的核 SI 和 LI 中的受体 (NR) 与不同类别的宿主和微生物衍生的代谢物相互作用， 分别。 Sundrud 实验室最近的工作确定了 Foxp3-T 效应子 (Teff) 子集 - Th1、Th17 细胞——使用先前不知道免疫功能的 NR，即组成型雄甾烷受体 (CAR/Nr1i3)，指导“肝细胞样”转录反应以对抗潜在的细胞毒性胆汁酸 (BA) SI 中的浓度。由于 SI（毫摩尔）和 LI（微摩尔）之间存在较大的 BA 梯度 进入“肠肝”循环——初级 BA 在肝脏中合成，储存在胆囊中，并在消化后分泌。 餐时进入十二指肠，并被回肠中专门的肠细胞主动重吸收，用于门脉 再循环至肝脏。由于 BA 是亲脂性的，因此它们在肠肝中可能具有毒性和促炎性 纸巾；许多核受体（包括 CAR）已经进化出可以抑制肝细胞中 BA 的毒性，并且 肠细胞。我们的数据表明，肠肝循环创造了一个独特的严酷 SI 微环境， 浸润 T 细胞必须适应以维持耐受性和组织稳态。相比之下，LI 拥有 细菌比 SI 多 103-107 倍，BA 少约 1000 倍。因此，微生物及其代谢物—— 短链脂肪酸（SCFA；例如丁酸）、次生 BA（通过残余物的微生物代谢产生） 初级 BA）——成为 LI 免疫调节的核心。 SCFA 抑制组蛋白脱乙酰酶 (HDAC) 并稳定外周诱导的 T 调节细胞 (iTreg) 中的 Foxp3 基因表达，而 次级 BA 通过另一种 NR、维生素 D 受体 (VDR) 促进 LI Treg 维持。因此，虽然 启动促炎性和抗炎性 T 细胞反应需要来自肠道菌群的抗原 在整个肠道中，我们假设细菌和胆汁的丰度存在显着差异 SI 与 LI 建立了相应的代谢物梯度，这些梯度由不同的 NR 感知以指导 区室化的 T 细胞调节功能。我们通过互补而非相互检验来检验这一假设 依赖，目标，利用新的小鼠模型，以及基于重组蛋白的 NR 活性库 测定，以确定控制转录调控、生化激活和 CAR（在 SI Teff 细胞中）和 VDR（在 LI iTreg 细胞中）的下游细胞功能。顺利完成 这些目标将建立新的生物学范式，并为治疗人类 IBD 提供更精确的方法。