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

细胞毒性CD 8 + T细胞（CTL）不仅对清除病毒感染的细胞至关重要，而且还有助于慢性病毒感染的病理学。为了改善针对这些全球相关疾病的基于CTL的治疗干预，我们需要更好地了解树突状细胞（DC）引发CTL的机制。由于DC需要通过先天信号激活和/或通过CD 4 + T细胞许可以引发最佳CTL应答，因此这两种模式代表CTL免疫的关键组分。然而，先天信号，如Toll样受体（TLR）和干扰素（IFN）如何精确地促进CTL免疫，以及CD 4 + T细胞介导的DC许可的机制调控是什么，仍然知之甚少。建立在单纯疱疹病毒（HSV）皮肤感染的模型中获得的未发表的结果，我们提出，DC许可是由CD 4 + T细胞介导的赋予DC提供IL-15的CTL的能力。假设DC许可的这种模式不仅与鼠HSV感染相关，而且还影响对其他病毒感染（如流感）的免疫，并且从该模型预测的基本原理也在人DC中起作用。通过阐明干扰素（I型IFN，IFN-γ）和Toll样受体（TLR 3）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。

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 Building on unpublished results obtained in a model of Herpes simplex virus (HSV) skin infection, we propose that DC licensing is mediated by CD4+ T cells endowing DC with the ability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.