Early events regulating post-viral immunopathology

调节病毒后免疫病理学的早期事件

• 批准号: 9130393
• 负责人: RICHARD I ENELOW
• 金额: $ 40.5万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130393
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Antiviral Agents; Autocrine Communication; CD8B1 gene; Candidate Disease Gene; Cell Death; Cells; Complex; Data; Disease; Effector Cell; Elements; Epigenetic Process; Event; Exposure to; Gene Expression; Genes; Goals; Hand; Health; Histone Code; Histones; Homeostasis; Hour; Human; Immune; Immune response; Immunologics; Infection; Inflammation; Inflammatory Response; Injury; Interferon Type I; Interferons; Kinetics; Knowledge; Lead; Licensing; Ligands; Lung; Maintenance; Mediating; Modeling; Modification; Pattern; Peripheral; Phase; Phenotype; Play; Predisposition; Process; Production; Proteolysis; Reagent; Regulation; Resolution; Role; Signal Transduction; Source; Staging; Stimulus; Synapses; System; T cell regulation; T cell response; T-Lymphocyte; TNF gene; TNFRSF1A gene; Testing; Time; Tissues; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Vaccination; Viral; Virus; Virus Diseases; autocrine; epigenome; histone modification; human TNF protein; immunopathology; influenzavirus; interest; lung injury; paracrine; pathogen; programs; respiratory infection virus; response; toxicant

 DESCRIPTION (provided by applicant): The controlled contraction of immune responses during the clearance of respiratory virus infection is critical to resolution of inflammation and te limitation of lung injury. The kinetics of antiviral effector CD8+ T cell contraction, and dampenin of effector function, appears to be programmed during the initial activation of naive T cells, and possibly prior. Among other negative regulators of immune responses, it has long been appreciated that TNF-alpha signaling plays an important role in contraction of CD8+ effector T cells, though the precise mechanisms involved remain unclear. We've shown that the critical timing of TNF-programmed contraction occurs within the first 24-48 hours after initial antigen recognition, and plays little immunoregulatory role thereafter. Furthermore, the critical source of this early burst of TNF production is the naive CD8+ T cell upon initial antigen recognition. We hypothesize that the ability of the naive CD8+ T cell to produce an early TNF burst is critically dependent upon homeostatic type I interferon signaling in the host milieu prior to infection. The IFN-mediated regulation of the early burst of TNF-α by naive CD8+ T cells is quite complex, and appears dependent upon post-thymic peripheral T cell "licensing", during which the impact of constitutive low-level IFN production confers the tendency to mount this important early TNF response. We propose that this involves epigenetic "licensing" of naive T cells for this critical activity. The fundamental hypothesis of this proposal is that signals from the host milieu impinge upon naive CD8+ T cell through epigenetic events, which have a direct impact on the kinetics of the contraction of the T cell responses and effector activities during and after viral infection, serving to limit lung injury and immunopathology.

 描述（由申请人提供）：清除呼吸道病毒感染期间免疫反应的受控收缩对于消退炎症和限制肺损伤至关重要。抗病毒效应 CD8+ T 细胞收缩的动力学和效应功能的抑制素似乎是在初始 T 细胞的初始激活期间（甚至可能之前）进行编程的。在免疫反应的其他负调节因子中，人们长期以来一直认识到 TNF-α 信号在 CD8+ 效应 T 细胞的收缩中发挥着重要作用，但所涉及的确切机制仍不清楚。我们已经证明，TNF 程序性收缩的关键时机发生在初始抗原识别后的前 24-48 小时内，此后几乎不发挥免疫调节作用。此外，关键来源 这种早期爆发的 TNF 产生是初始抗原识别后的初始 CD8+ T 细胞。我们假设初始 CD8+ T 细胞产生早期 TNF 爆发的能力主要取决于感染前宿主环境中 I 型干扰素稳态信号传导。初始 CD8+ T 细胞对 TNF-α 早期爆发的 IFN 介导调节相当复杂，并且似乎依赖于胸腺后外周 T 细胞的“许可”，在此期间，组成型低水平 IFN 产生的影响赋予了这种重要的早期 TNF 反应的倾向。我们认为这涉及幼稚 T 细胞的表观遗传“许可”，以实现这一关键活动。该提议的基本假设是，来自宿主环境的信号通过表观遗传事件影响初始 CD8+ T 细胞，这对病毒感染期间和之后 T 细胞反应收缩的动力学和效应器活动产生直接影响，从而有助于限制肺损伤和免疫病理学。