ROLE OF TYPE-I IFN'S IN ANTIVIRAL CD8 CELL RESPONSE

I 型干扰素在抗病毒 CD8 细胞反应中的作用

• 批准号: 7151129
• 负责人: MURALI KRISHNA KAJA
• 金额: $ 28.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151129
• 关键词: Acute; Animals; Antigen-Presenting Cells; Antigens; Antiviral Agents; Antiviral Response; Bacterial Infections; Biological; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clonal Expansion; Condition; Data; Doctor of Philosophy; Event; Exposure to; Future; Generations; Goals; Health; Human; Immune; Immune response; Immune system; Immunity; Immunologic Memory; Immunologist; In Vitro; Infection; Infectious Agent; Inflammatory; Interferon Type I; Interferons; Knowledge; Life; Light; Lymphocyte; Lymphocytic choriomeningitis virus; Lymphoid Tissue; MHC Class I Genes; Maintenance; Mediating; Memory; Modeling; Mus; Natural Immunity; Numbers; Ovalbumin; Peptides; Phenotype; Play; Process; Research; Role; Side; Signal Transduction; Specificity; Stimulus; Study Section; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Thinking; Transcriptional Activation; Transgenic Organisms; Up-Regulation; Vaccination; Vaccine Design; Vaccines; Viral; Virus; Virus Diseases; Work; base; cytokine; improved; in vivo; insight; mouse model; pathogen; receptor; receptor expression; research study; response; type I interferon receptor; vaccination strategy

The long-term objectives of our research are to understand the mechanisms by which acute viral infections induce potent immune responses with a hope that the knowledge gained from infectious models can be applied for improving vaccination strategies. Our previous studies, using mouse models of lymphocytic choriomeningitis virus (LCMV) infection, demonstrated that acute viral infections induce a much higher magnitude of primary and memory CD8 T cell responses than was previously thought. We found that these anti-viral memory CD8 cells persist for extended periods even in the absence of T cell receptor-MHC class I interactions. Now it is becoming clear that some infections can elicit significant T cell responses even in the absence of costimulatory molecules or professional APC help. The underlying mechanisms are not clear. To better understand these mechanisms, we started characterizing possible events that may contribute to the enhanced T cell response in viral infection. We found that infection-induced type-I interferons (IFNodl3)(a) helps potentiate the CD8 T cell response and (b) cause a transient activation of na'fve T cells early after infection. We hypothesize that this IFNcdl3 mediated sensitization of na'fve CD8 T cells may provide an additional signal that potentiates the ability to respond to antigen. As a result, the na'fve CD8 T cells may respond well even in the absence of co-stimulatory and or professional APC help under the conditions of infection. This proposal is aimed at testing this by pursuing the following hypotheses: (1) that naive CD8 T cells, upon sensitization by infection-induced IFNcdl3 may lower their activation threshold and respond better to cognate antigenic stimulus, (2) that IFNcz/13receptorpositive (IFNRc_/13+/+)CD8 T cells may have a selective advantage over receptor negative (IFNRcdl3-/-) CD8 T cells in eliciting immune response during viral infection, and, (3) that IFNRcdl3+/+ CD8 T cells may become less dependent upon professional APC help than IFNRcdI3-/- CD8 T cells during an anti-viral response. These studies will provide insight into the biological consequences of bystander T cell activation in viral infections and the mechanisms of cross-talk between innate and adaptive immunity. This work has implications for improving vaccination strategies and provides groundwork for future studies aimed at understanding the mechanisms involved in generation of immune memory and have significance for human and animal health.

我们研究的长期目标是了解急性病毒感染的机制 诱导有效的免疫反应，希望从感染模型中获得的知识可以是 申请改善疫苗接种策略。我们先前使用淋巴细胞模型的研究 脉络膜脑膜炎病毒（LCMV）感染表明，急性病毒感染会诱导更高 主要和记忆CD8 T细胞反应的大小比以前认为的幅度。我们发现这些 抗病毒记忆CD8细胞即使在没有T细胞受体MHC I类的情况下持续了长时间 互动。现在很明显，即使在 缺乏共刺激分子或专业的APC帮助。基本机制尚不清楚。到 更好地了解这些机制，我们开始表征可能有助于该事件的可能事件 病毒感染中T细胞反应增强。我们发现感染引起的I型干扰素（IFNODL3）（a） 帮助增强CD8 T细胞反应，（b）在早期引起Na'fve T细胞的短暂激活 感染。我们假设这种IFNCDL3介导的Na'fve CD8 T细胞的敏化可能会提供 增强对抗原反应能力的其他信号。结果，Na'fve CD8 T细胞可能 即使在没有共同刺激和 /或专业APC帮助下，响应也很好 感染。该建议旨在通过提出以下假设来测试这一点：（1）幼稚的CD8 T 细胞，在感染引起的IFNCDL3敏化后，可能会降低其激活阈值并响应更好 （2）IFNCZ/13型（IFNRC_/13+/+）CD8 T细胞可能具有一个可能具有的抗原刺激。 选择性优势比受体阴性（IFNRCDL3 - / - ）CD8 T细胞在引起免疫反应中的选择性优势 病毒感染，以及（3）IFNRCDL3+/+ CD8 T细胞可能会减少对专业APC的依赖 在抗病毒反应期间，帮助IFNRCDI3 - / - CD8 T细胞。 这些研究将洞悉病毒旁观者T细胞激活的生物学后果 先天性和适应性免疫之间的感染和交叉讲话机制。这项工作有 改善疫苗接种策略的影响，并为未来的研究提供了基础。 了解产生免疫记忆的机制，并对人具有重要意义 和动物健康。