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.

摘要 疱疹病毒进入介体(Hvem)是肿瘤坏死因子受体超家族的成员。我们出版的 结果表明，粘膜上皮细胞表达的hvem在天然防御中起重要作用。 抗肠道和肺部的病原菌。我们最近的研究表明，HVEM还 在稳态条件下肠道上皮细胞的功能。具有上皮细胞特异性的小鼠 HVEM缺失会降低小肠上皮内淋巴细胞(IEL)的存活率， 节段性丝状细菌(SFB)的增加，导致Th17细胞的增加。这个 这项应用中的实验旨在探索HVEM影响的机理基础。 肠道中的免疫和微生物动态平衡，以及IEL降低之间的联系(如果有) 种群数量和SFB增加。HVEM有三个结合伙伴：CD160、BTLA和LIGHT。在……里面 具体目标1，我们将使用生殖系或条件性缺陷的小鼠来编码每种基因 这些分子识别哪一种(S)是相关的，哪种细胞类型表达这种蛋白质。在……里面 具体目标2，我们将研究上皮性HVEM如何调节IEL种群的大小。我们的 初步数据提示了一种间接机制，在这种机制中，hvem信号导致上皮细胞 增加基底膜蛋白的合成，该基膜蛋白与含有β1的整合素结合 太好了。整合素-基底膜的相互作用导致IEL存活率增加。我们将对此进行测试 间接机制，部分是通过分析β1整合素缺陷小鼠的IEL。作为替代方案 机制，我们将调查hvem是否作为一种配体进行反向信号促进 通过其有约束力的伙伴之一直接返回IEL。在具体目标3中，我们将确定是否 在无上皮性高血压的情况下，IEL减少和SFB增加是有因果关系的。我们也会 进行体外和体内实验，以了解上皮细胞如何影响微生物群， 尤其是如果对IL-23-IL-22轴和3型固有淋巴样细胞(ILC3)有影响，并使用 对于有机物培养，我们将确定通过NF-κB和/或STAT3的信号是否相关。总的来说，这些 实验将使我们更深入地了解无数先天居住的功能 肠道中的淋巴细胞，常驻淋巴细胞和上皮细胞之间的相互作用，以及如何 这些分子和细胞的相互作用有助于组织的动态平衡和微生物群。这个 缺乏上皮病毒的小鼠肠道中Th17细胞的增加及其与病毒的相关性 肠道炎症性疾病的多态，表明根本问题 对于了解粘膜免疫系统的功能非常重要。 在提供保护的同时避免破坏性炎症。