HVEM: A TNF family receptor that influences mucosal immunity and the microbiome

HVEM：影响粘膜免疫和微生物组的 TNF 家族受体

• 批准号: 9294945
• 负责人: MITCHELL KRONENBERG
• 金额: $ 53.53万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-13 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294945
• 关键词: Address; Affect; Back; Bacteria; Basement membrane; Binding; Binding Proteins; Cell Count; Cells; Collagen; Dangerousness; Data; Disease; Epithelial; Epithelial Cells; Epithelium; Family; Genes; Genetic Polymorphism; Germ Lines; Germ-Free; Health; Herpesviridae; Homeostasis; Immune; Immune system; Immunoglobulin A; In Vitro; Inflammation; Inflammatory; Integrin Binding; Integrins; Intestinal Content; Intestines; Knockout Mice; Lamina Propria; Leukocytes; Ligands; Link; Lung; Lymphocyte; Lymphocyte Count; Lymphoid Cell; Measures; Mediating; Mediator of activation protein; Molecular; Mono-S; Mucosal Immunity; Mus; Mutation; Organoids; Peptides; Phenotype; Population; Production; Proteins; Publishing; Reaction; Role; Shapes; Side; Signal Transduction; Signaling Molecule; Small Intestines; TNF gene; Testing; Tissues; Tumor Necrosis Factor Receptor; Work; antimicrobial; base; cell type; cytokine; design; experimental study; gut microbiota; herpesvirus entry mediator; in vivo; interleukin-22; interleukin-23; intestinal epithelium; intraepithelial; member; microbial; microbiome; microbiota; novel; pathogenic bacteria; prevent; receptor; transcriptome sequencing

Summary The herpes virus entry mediator (HVEM) is a member of the TNF receptor super family. Our published findings indicated that HVEM expressed by mucosal epithelial cells is important for innate defense against pathogenic bacteria in the intestine and the lung. Our recent work suggests that HVEM also functions in intestine epithelial cells under steady state conditions. Mice with an epithelial cell-specific HVEM deletion have a decrease in the survival of intraepithelial lymphocytes (IEL) in the small intestine, and an increase in segmented filamentous bacteria (SFB), which causes an increase in Th17 cells. The experiments in this application are designed to explore the mechanistic bases for the effects of HVEM on immune and microbial homeostasis in the intestine, and the connection, if any, between decreased IEL populations and increased SFB. HVEM has three binding partners: CD160, BTLA, and LIGHT. In specific aim 1, we will use mice with germ line or conditional deficiency for the genes encoding each of these molecules to identify which one(s) is relevant and which cell type expresses this protein. In specific aim 2, we will investigate how epithelial HVEM regulates the size of the IEL population. Our preliminary data suggest an indirect mechanism, in which HVEM signals cause the epithelium to increase synthesis of basement membrane proteins that bind to β1-containing integrins expressed by the IEL. The integrin-basement membrane interaction leads to increased IEL survival. We will test this indirect mechanism, in part by analyzing IEL from β1 integrin deficient mice. As an alternative mechanism, we will investigate if HVEM acts as a ligand that carries out reverse signals that promote survival directly back to IEL through one of its binding partners. In specific aim 3, we will determine if the decrease in IEL and increase in SFB in the absence of epithelial HVEM are causally linked. We also will carry out in vitro and in vivo experiments to understand how epithelial HVEM affects the microbiome, in particular if there are effects on the IL-23-IL-22 axis and type 3 innate lymphoid cells (ILC3), and using organoid cultures, we will determine if signals through NF-κB and/or Stat3 are relevant. Overall, these experiments will provide a deeper understanding of the function of the numerous resident, innate-like lymphocytes in the intestine, the cross talk between resident lymphocytes and epithelial cells, and how these molecular and cellular interactions contribute to tissue homeostasis and the microbiome. The increase in Th17 cells in the intestine of mice lacking epithelial HVEM, and the association of HVEM polymorphisms with inflammatory diseases in the intestine, indicate that the fundamental issues addressed in this application are important for understanding the function of the mucosal immune system in providing protection while avoiding destructive inflammation.

概括 疱疹病毒进入介质（HVEM）是TNF受体超级家族的成员。我们出版了 调查结果表明，粘膜上皮细胞表达的HVEM对于先天防御很重要 针对肠和肺中的致病细菌。我们最近的工作表明HVEM也 在稳态条件下在肠上皮细胞中起作用。具有上皮细胞特异性的小鼠 HVEM缺失的上皮内淋巴细胞（IEL）的存活率降低 分段细菌（SFB）的增加，这会导致Th17细胞的增加。 本应用程序中的实验旨在探索HVEM对HVEM影响的机械基础 肠中的免疫和微生物稳态，以及改善IEL之间的连接（如果有） 种群和SFB增加。 HVEM有三个结合伙伴：CD160，BTLA和光。在 特定目标1，我们将使用具有种系或条件缺陷的小鼠来编码每个的基因 这些分子以识别哪个是相关的，哪种细胞类型表示该蛋白质。在 具体目标2，我们将研究上皮HVEM如何调节IEL人群的大小。我们的 初步数据提出了一种间接的机制，其中HVEM信号导致上皮到 增加与含β1的整合素结合的地下膜蛋白的合成 IEL。整联蛋白 - 膜膜相互作用导致IEL存活增加。我们将测试这个 间接机制，部分通过分析β1整合素缺陷小鼠的IEL。作为替代方案 机制，我们将调查HVEM是否充当具有促进的反向信号的配体 生存通过其约束伙伴之一直接回到IEL。在特定目标3中，我们将确定是否 不幸的是，在没有上皮HVEM的情况下，IEL的减少和SFB的增加是相关的。我们也会 进行体外和体内实验，以了解上皮HVEM如何影响微生物组， 特别是如果对IL-23-IL-22轴和3型先天淋巴样细胞（ILC3）有影响，并使用 器官培养物，我们将确定通过NF-κB和/或STAT3的信号是否相关。总体而言，这些 实验将对众多居民的功能有更深入的了解，类似于先天的居民 肠道中的淋巴细胞，居民淋巴细胞和上皮细胞之间的串扰，以及如何 这些分子和细胞相互作用有助于组织稳态和微生物组。 缺乏上皮HVEM的小鼠肠中Th17细胞的增加，HVEM的关联 肠中患有炎症性疾病的多态性表明基本问题 本应用程序中解决的问题对于理解粘膜免疫系统的功能很重要 在避免破坏性炎症的同时提供保护。