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

• 批准号: 10368914
• 负责人: Emily Ann Hemann
• 金额: $ 10.71万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-09 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368914
• 关键词: Address; Antibody Response; Antigen Presentation; 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; Reporter; Role; Signal Transduction; Site; Supplementation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Therapeutic; Time; Tissues; Vaccine Therapy; Variant; Viral; 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; gene regulatory network; immunoregulation; in vivo; mouse model; mucosal site; neutralizing antibody; novel; prevent; programs; receptor; residence; respiratory infection virus; respiratory virus; response; transcription factor; transcriptomics

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. !

项目总结。先天适应性免疫界面代表的作用部位，其中的成分