Mechanisms of Interferon-Lambda Programming at the Innate-Adaptive Immune Interface for Protection Against Virus Infection

先天适应性免疫接口的干扰素-Lambda 编程机制，用于预防病毒感染

基本信息

批准号：
9973444
负责人：
Emily Ann Hemann
金额：
$ 16.07万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-09 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973444
关键词：
Address Antibody Response Antigen Presentation Antiviral Agents Attenuated Bioinformatics CD8-Positive T-Lymphocytes Cell Culture Techniques Cell Maintenance Cell physiology Cells Data Set Dendritic Cells Development Environment Epithelial Epithelial Cells Exhibits Generations Genes Genetic Transcription Human Immune Immune response Immunity Immunologic Memory Immunology Immunotherapy Infection Influenza A virus Innate Immune Response Interferons Interleukin-10 Kinetics Knock-out Knockout Mice Knowledge Lung Mediating Memory Modeling Mucous Membrane Mus Natural Immunity Play Population Production Public Health Regulation Regulator Genes Reporter Role Signal Transduction Site Supplementation T cell response T memory cell T-Cell Activation T-Lymphocyte Therapeutic Time Tissues Vaccine Therapy Variant Virus Virus Diseases Wild Type Mouse Work adaptive immune response adaptive immunity base cell motility cell type conditional knockout cross immunity cytokine defined contribution draining lymph node immunoregulation in vivo mouse model mucosal site neutralizing antibody novel prevent programs receptor residence respiratory infection virus respiratory virus response transcription factor transcriptomics

项目摘要

Project Summary. The innate-adaptive immune interface represents the site of action where components of both innate and adaptive immunity cross-engage each other to program the effector actions of the adaptive immune response. The actions of the innate-adaptive immune interface are considered essential for establishing protective immunity and immune memory against virus infection. Type III interferon (IFN-λ) is a cytokine that functions at the innate-adaptive immune interface and is critical for mediating innate immune protection at mucosal barriers. IFN-λ provides therapeutic benefit against Influenza A virus (IAV) infection, however how it operates within the innate-adaptive interface is not defined. We have utilized a murine model of IAV infection to study the contribution of IFN-λ in regulation of immunity at the innate-adaptive interface during respiratory virus infection. Our studies show Ifnlr1-/- mice have blunted effector CD8+ T cell responses compared to WT mice and exhibit reduced survival upon heterosubtypic IAV re-challenge. Analysis of dendritic cells (DCs) reveals that IFN-λ signaling directs CD103+ DC migration and function to develop optimal anti-viral CD8+ T cell responses. Further, preliminary bioinformatic analysis suggests IFN-λ is essential for control of an Il10 immunoregulatory network in DCs during IAV infection. Our observations reveal that IFN-λ bridges innate and adaptive immunity to direct DCs to program effective T cell immunity against IAV. We hypothesize IFN-λ signaling in DC regulates an IL-10 program critical for development of effective T cell memory for lasting immunity against IAV. Thus, the studies in this proposal aim to: 1) determine the contribution of IFN-λ to generation of memory CD4+ and CD8+ T cell responses and 2) elucidate IFN-λ regulation of IL-10 in programming DC functions. Results from these studies will define the role of IFN-λ at the innate-adaptive immune interface in programming effective immunity against IAV infection and inform IFN-λ-based vaccine and immune therapy strategies to prevent and limit infection. !

项目摘要先天适应性免疫界面代表了各成分的作用位点。先天性免疫和适应性免疫相互交叉参与，以编程适应性免疫的效应器行为先天适应性免疫界面的作用被认为是必不可少的。建立针对病毒感染的保护性免疫力和免疫记忆。在先天适应性免疫界面发挥作用的细胞因子，对于介导先天免疫至关重要 IFN-λ 可以保护粘膜屏障，提供针对甲型流感病毒 (IAV) 感染的治疗效果，然而，它如何在先天适应性界面中运作尚未定义。我们使用了小鼠模型。 IAV 感染研究 IFN-λ 在先天适应性界面免疫调节中的贡献我们的研究表明，Ifnlr1-/- 小鼠的效应 CD8+ T 细胞反应减弱。与 WT 小鼠相比，异亚型 IAV 再次攻击后存活率降低。细胞 (DC) 揭示 IFN-λ 信号传导指导 CD103+ DC 迁移和功能，以开发最佳的抗病毒药物此外，初步生物信息分析表明 IFN-λ 对于控制 CD8+ T 细胞反应至关重要。 IAV 感染期间 DC 中的 Il10 免疫调节网络我们的观察表明 IFN-λ 桥接先天。和适应性免疫引导树突状细胞对 IAV 进行有效的 T 细胞免疫。 DC 中的信号传导调节 IL-10 程序，该程序对于有效 T 细胞记忆的发展至关重要因此，本提案中的研究旨在： 1) 确定 IFN-λ 对 IAV 的贡献。记忆 CD4+ 和 CD8+ T 细胞反应的产生，2) 阐明 IFN-λ 对 IL-10 的调节这些研究的结果将定义 IFN-λ 在先天适应性中的作用。免疫接口编程有效免疫 IAV 感染并为基于 IFN-λ 的疫苗提供信息预防和限制感染的免疫治疗策略。！