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.

项目摘要 肠道是一种中央免疫器官，宿主 - 微生物相互作用塑造免疫耐受性和 在本地和系统上发炎。然而，流行的免疫学观点将两个不同的器官混为一谈 完成肠道 - 小肠和大肠（或SI和LI），这阻碍了人们对 粘膜免疫调节，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，建立在最新发现的基础上， 两个PI之间的协同作用（Sundrud，Weaver）是粘膜CD4+ T细胞使用不同的核 Si和Li中的受体（NRS）与宿主和微生物衍生的代谢物的不同类别 Sundrud Lab的最新工作确定Foxp3 t效应子（TEFF）子集-TH1，TH17 细胞 - 使用原始雄激素接收器的NR具有未知的免疫学功能 （CAR/NR1I3），指导“肝细胞样”转录反应与潜在的细胞毒性胆汁酸抗衡 （BA）Si中的浓度。 Si（毫米）和Li（Microlol）之间存在很大的BAS梯度 要“肠球形膜上”圆圈 - 在肝脏中合成的主要BAS，存储在胆囊中，并分泌后 培养在十二指肠上，在门户网站上被专门的肠细胞重新吸收 向肝脏再循环。因为BAS是亲脂性的，所以它们可能是有毒的和促炎性的 组织；包括汽车在内的一系列核接收器已进化为抑制肝细胞中的BA毒性 肠球菌。我们的数据表明，肠ePatitic圈创造了一种独特的危险si微环境 浸润的T细胞必须适应以维持耐受性和组织稳态。相比之下，李港 细菌比SI多103-107倍，BAS少约1000倍。彼此之间，微生物及其代谢物 - 短链脂肪酸（SCFA； 初级BAS） - LI中免疫调节的中心。 SCFA抑制组蛋白脱乙酰基酶 （HDACS）并稳定外周诱导的T调节细胞（ITREGS）中的Foxp3基因表达，而 次级BAS通过另一种NR维生素D受体（VDR）促进Li Treg维持。那，而 启动促疾病和抗炎的T细胞反应需要肠菌群的抗原 在整个肠道中，我们假设在虫子和胆汁中的抽象上有明显的差异 Si vs. Li建立后果的代谢物梯度，这些梯度被不同的NR感知以指导 分室的T细胞调节功能。我们通过完善，但不进行检验 依赖，目的，利用新的小鼠模型以及基于重组蛋白的NR活性的库 测定，定义管理转录调节，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。成功完成 这些目标将建立新的生物学范式，并为治疗人类IBD的更精确的方法提供信息。