Interferon regulation of gamma delta intraepithelial lymphocyte activation

干扰素调节γδ上皮内淋巴细胞活化

基本信息

批准号：
10396439
负责人：
Karen Leigh Edelblum
金额：
$ 35.26万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-04 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396439
关键词：
Acute Affect Antigens Antiviral Response Autoimmunity Behavior Biological Biological Process CD47 gene Celiac Disease Cell physiology Cells Complement Data Epithelial Epithelial Cells Extracellular Space Feedback Gene Expression Gene Targeting Genetic Models Goals Health Hematopoietic Homeostasis Host Defense Hour Imaging Techniques Immune system Immunologic Surveillance Immunologics Impairment In Vitro Infection Inflammatory Bowel Diseases Interferon Type I Interferon Type II Interferon-alpha Interferons Interleukin-4 Intestinal Mucosa Intestines Knowledge Lateral Liquid substance Lymphocyte Lymphocyte Activation Maintenance Mediating Microbe Mission Modeling Molecular Mucous Membrane Mus National Institute of Diabetes and Digestive and Kidney Diseases Natural Immunity Norovirus Phenotype Play Population Positioning Attribute Predisposition Production Proteins Public Health Receptor Activation Receptor Signaling Regulation Reporting Research Role Signal Pathway Signal Transduction Systemic infection T-Cell Receptor Techniques Therapeutic United States National Institutes of Health Virus Diseases Work adaptive immune response adaptive immunity antimicrobial base cell motility enteric infection enteric pathogen enteric virus infection human disease improved in vivo Model insight intestinal barrier intestinal homeostasis intestinal injury intraepithelial intravital microscopy microbial microorganism migration mouse model novel pathogen pathogen exposure prevent receptor response transcriptome γδ T cells

项目摘要

PROJECT SUMMARY. Immune surveillance at mucosal barriers is essential to provide an immediate defense against invasive microbes, yet must also be tightly regulated limit the potential for autoimmunity. Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) bridge innate and adaptive immunity, and function as a first line of defense by promoting mucosal barrier integrity. Recent reports demonstrate that basal γδ IEL function is influenced by extrinsic microbial signals. Although commensal-induced tonic type I interferon (IFN) signaling has been shown to prime mucosal innate immunity and host responsiveness to pathogen, the involvement of type I IFN in γδ IEL activation and epithelial surveillance remains unknown. Our preliminary data demonstrate that constitutive low level type I IFN signaling regulates the appropriate number and proportion of Vγ TCR subsets in the epithelial compartment and maintain these cells in an actively patrolling, yet immunologically quiescent state. We now show that impaired interferon α/β receptor (IFNAR) activation induces a dysregulated γδ IEL phenotype, characterized by hyperproliferation, hypermotility and enhanced IL-4 expression. Further, we find that pathogen-associated levels of type I IFN amplify γδ IEL effector functions, including epithelial surveillance. Therefore, we propose to interrogate the mechanism by which tonic type I IFN signaling maintains γδ IEL homeostasis, whereas amplification of type I IFN in response to pathogen enhances γδ IEL effector function. In the first aim, we will take advantage of genetic models that permit the inducible γδ T-cell-specific deletion of IFNAR to examine the role of tonic IFNAR/STAT signaling in the maintaining γδ IEL homeostasis through appropriate regulation of different Vγ subsets. We will also investigate the mechanisms by which IFNAR signaling regulates crosstalk between different γδ IEL subsets and how this influences the proliferation, motility and effector function of these cells. Next, we will determine the functional consequence of γδ IEL dysregulation on epithelial barrier integrity under steady-state conditions. In the second aim, we will examine the mechanisms by which type I IFN amplifies γδ IEL effector function following viral infection. Using the novel intravital microscopy techniques that we pioneered and our ability to move fluidly between in vitro and in vivo models, we will investigate the molecular signals induced by pathogen-associated levels of type I IFN to enhance γδ IEL epithelial surveillance and activation. Lastly, based on the protection conferred by γδ IELs in response to enteric pathogens, we will examine the role of type I IFN-induced γδ IEL activation in the context of acute enteric viral infection. By combining, temporal and cell-specific gene targeting, cutting edge live imaging techniques, and novel models to analyze γδ IEL function ex vivo, we expect to define the molecular mechanisms by which type I IFN regulates γδ IELs under homeostatic conditions and during infection. The proposed studies will provide new insight into the molecular mechanisms that regulate γδ IEL activation and the extent to which enhanced γδ IEL effector function affects epithelial integrity and host defense.

项目摘要。粘膜屏障的免疫监视对于提供针对侵入性的立即防御至关重要微生物，但也必须受到严格监管，以限制自身免疫的可能性。表达 γδ T 细胞受体 (γδ IEL) 桥接先天免疫和适应性免疫，并作为第一线最近的报告表明，基础 γδ IEL 功能是通过促进粘膜屏障完整性来进行防御的。虽然共生诱导的强直 I 型干扰素 (IFN) 信号传导受到外在微生物信号的影响。已被证明可以启动粘膜先天免疫和宿主对病原体的反应，我们的初步数据表明，I 型 IFN 在 γδ IEL 激活和上皮监测中的作用仍然未知。组成型低水平 I 型 IFN 信号传导调节 Vγ TCR 的适当数量和比例上皮区室中的子集，并维持这些细胞的积极巡逻，但免疫学我们现在表明，干扰素α/β受体（IFNAR）激活受损会导致失调。 γδ IEL 表型，其特征是过度增殖、过度运动和增强的 IL-4 表达。发现病原体相关的 I 型 IFN 水平会放大 γδ IEL 效应功能，包括上皮细胞因此，我们建议探究强直型 I IFN 信号维持的机制。 γδ IEL 稳态，而响应病原体的 I 型 IFN 扩增增强 γδ IEL 效应子在第一个目标中，我们将利用允许诱导型 γδ T 细胞特异性的遗传模型。删除 IFNAR 以检查强效 IFNAR/STAT 信号在维持 γδ IEL 稳态中的作用通过对不同 Vγ 子集的适当调节，我们还将研究其机制。 IFNAR 信号传导调节不同 γδ IEL 子集之间的串扰及其如何影响增殖，接下来，我们将确定 γδ IEL 的功能结果。在第二个目标中，我们将研究稳态条件下上皮屏障完整性的失调。病毒感染后 I 型 IFN 放大 γδ IEL 效应器功能的机制。我们首创的活体显微镜技术以及我们在体外和体内之间流畅移动的能力模型中，我们将研究由病原体相关 I 型 IFN 水平诱导的分子信号增强 γδ IEL 上皮监视和激活最后，基于 γδ IEL 所赋予的保护。为了研究对肠道病原体的反应，我们将研究 I 型 IFN 诱导的 γδ IEL 激活在以下情况中的作用：急性肠道病毒感染通过结合时间和细胞特异性基因靶向、尖端实时成像。技术和新模型来分析 γδ IEL 离体功能，我们期望定义分子 I 型 IFN 在稳态条件下和感染期间调节 γδ IEL 的机制。拟议的研究将为调节 γδ IEL 激活和增强的 γδ IEL 效应器功能影响上皮完整性和宿主防御的程度。