Defining the mechanisms of CD4+ T cell help and roles of XCR1+ dendritic cells in CD8+ T cell responses

定义 CD4 T 细胞帮助的机制以及 XCR1 树突状细胞在 CD8 T 细胞反应中的作用

• 批准号: 395656065
• 负责人: Dr. Milas Ugur
• 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: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/395656065?language=en
• 关键词: Defining; mechanisms; CD4+; cell; help

Successful immune responses depend on interaction and coordination of several immune cell types. Initiation of antiviral CD8+ T cell responses is an excellent example for this as it involves the cooperation of CD4+ T cells, dendritic cells (DCs) and CD8+ T cells. In this case, naïve CD8+ T cells need to be activated by DCs and these DCs need to be licensed by CD4+ T cells for an effective response, especially in the memory phase. Although the requirement for CD4+ T cell help in CD8+ T cell responses is well established, the exact cellular and molecular mechanisms of this ‘help’ are not well understood. Recently, XCR1+ DCs, which are specialized in cross presentation of antigens to CD8+ T cells, emerged as the central DC subset involved in CD4+ T cell help to CD8+ T cells.In this project, we will investigate the roles XCR1+ DCs and CD4+ T cells in antiviral CD8+ T cells from a molecular perspective using skin herpes simplex virus (HSV) infection in mice as a model system. Skin HSV infection represents a unique infection model since HSV stays as a local infection in the skin and viral antigens has to be carried to draining lymph node by DCs, which is the case with most natural viral infections. It has been shown that this results in delayed activation of CD8+ T cells compared to CD4+ T cells as CD8+ T cells need viral antigens to be transferred to XCR1+ DCs from migratory DCs. Firstly, we will study the role of XCR1+ DCs and CD4+ T cells in CD8+ T cell priming and memory by depleting XCR1+ DCs or CD4+ T cells. Secondly, we will examine the kinetics and effects of T cell receptor signaling during the priming phase of antiviral CD8+ T cell responses against HSV. Lastly, we will analyze gene expression differences between CD8+ T cells that received CD4+ T cell help or not at the single cell level and try to identify genes expression patterns associated with enhanced memory potential. These studies will not only improve our understating of cellular and molecular events involved in the initiation of antiviral CD8+ T cell responses, but also provide valuable insights into changes induced in CD8+ T cells by CD4+ T cell help. We hope results from these studies to help us to design better vaccines that induce superior CD8+ T cells against viruses.

成功的免疫反应取决于几种免疫细胞类型的相互作用和协调。抗病毒 CD8+ T 细胞反应的启动就是一个很好的例子，因为它涉及 CD4+ T 细胞、树突状细胞 (DC) 和 CD8+ T 细胞的合作。在这种情况下，幼稚的 CD8+ T 细胞需要被 DC 激活，并且这些 DC 需要得到 CD4+ T 细胞的许可才能产生有效的反应，尤其是在记忆阶段。尽管 CD8+ T 细胞反应中 CD4+ T 细胞帮助的要求已得到充分确定，但这种“帮助”的确切细胞和分子机制尚不清楚。最近，专门负责将抗原交叉呈递给CD8+ T细胞的XCR1+ DCs，作为参与CD4+ T细胞帮助CD8+ T细胞的中央DC亚群出现。在本项目中，我们将以小鼠皮肤单纯疱疹病毒（HSV）感染为模型，从分子角度研究XCR1+ DCs和CD4+ T细胞在抗病毒CD8+ T细胞中的作用 系统。皮肤HSV感染代表了一种独特的感染模式，因为HSV作为皮肤中的局部感染而存在，并且病毒抗原必须由DC携带至引流淋巴结，这是大多数自然病毒感染的情况。研究表明，与 CD4+ T 细胞相比，这会导致 CD8+ T 细胞的激活延迟，因为 CD8+ T 细胞需要病毒抗原从迁移性 DC 转移到 XCR1+ DC。首先，我们将通过消耗 XCR1+ DC 或 CD4+ T 细胞来研究 XCR1+ DC 和 CD4+ T 细胞在 CD8+ T 细胞启动和记忆中的作用。其次，我们将检查 T 细胞受体信号传导在针对 HSV 的抗病毒 CD8+ T 细胞反应的启动阶段的动力学和影响。最后，我们将在单细胞水平上分析接受或未接受 CD4+ T 细胞帮助的 CD8+ T 细胞之间的基因表达差异，并尝试识别与增强记忆潜力相关的基因表达模式。这些研究不仅将提高我们对抗病毒 CD8+ T 细胞反应启动所涉及的细胞和分子事件的认识，而且还为 CD4+ T 细胞帮助诱导 CD8+ T 细胞的变化提供有价值的见解。我们希望这些研究的结果能够帮助我们设计出更好的疫苗，诱导出更好的 CD8+ T 细胞来对抗病毒。