Investigating the mechanisms of DC licensing for CTL induction following virus infection

研究病毒感染后 CTL 诱导的 DC 许可机制

• 批准号: 250878614
• 负责人: Annabell Bachem
• 金额: --
• 依托单位: Department of Microbiology and Immunology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250878614?language=en
• 关键词: Investigating; mechanisms; DC; licensing; CTL

Cytotoxic CD8+ T cells (CTL) are not only critical for the elimination of virus-infected cells, but also contribute to pathology in chronic virus infections. To improve CTL-based therapeutic interventions against these globally relevant diseases, we need a better understanding of the mechanisms underlying CTL priming by dendritic cells (DC). As DC require activation by innate signals and/or licensing by CD4+ T cells to elicit optimal CTL responses, these two modalities represent key components of CTL immunity. However, how precisely innate signals, such as toll-like receptors (TLR) and interferons (IFN) contribute to CTL immunity and what the mechanistic regulation of CD4+ T cell-mediated DC licensing is, remains poorly understood. Building on unpublished results obtained in a model of Herpes simplex virus (HSV) skin infection, we propose that DC licensing is mediated by CD4+ T cells endowing DC with the ability to provide IL-15 to CTL. It is hypothesized that this mode of DC licensing is not only relevant for murine HSV infection, but also impacts on immunity to other viral infections, such as influenza, and that basic principles predicted from this model also operate in human DC. By elucidating how interferons (type I IFN, IFN-gamma) and toll-like receptors (TLR3) regulate these events, and by validating the relevance of this model in other virus infections and the human setting, we expect this project to advance our understanding of T cell immunity.

细胞毒性CD8+ T细胞（CTL）不仅对病毒感染细胞的清除至关重要，而且还有助于慢性病毒感染的病理。为了改善针对这些全球相关疾病的基于CTL的治疗干预措施，我们需要更好地了解树突状细胞（DC） CTL启动的机制。由于DC需要先天信号激活和/或CD4+ T细胞许可才能引发最佳CTL反应，这两种方式代表了CTL免疫的关键组成部分。然而，诸如toll样受体（TLR）和干扰素（IFN）等先天信号如何精确地促进CTL免疫，以及CD4+ T细胞介导的DC许可的机制调控是什么，仍然知之甚少。基于在单纯疱疹病毒（HSV）皮肤感染模型中获得的未发表的结果，我们提出DC许可是由CD4+ T细胞介导的，赋予DC向CTL提供IL-15的能力。据推测，这种DC许可模式不仅与小鼠HSV感染有关，而且还影响对其他病毒感染（如流感）的免疫，并且该模型预测的基本原理也适用于人类DC。通过阐明干扰素（I型IFN， IFN- γ）和toll样受体（TLR3）如何调节这些事件，并通过验证该模型在其他病毒感染和人类环境中的相关性，我们希望该项目能够促进我们对T细胞免疫的理解。