How Chronic Antigen Presentation Compromises CD4+ T Cell Memory

慢性抗原呈递如何损害 CD4 T 细胞记忆

• 批准号: 200218701
• 负责人: Privatdozent Dr. Reinhard Obst
• 金额: --
• 依托单位: Forschungsbereich Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/200218701?language=en
• 关键词: How; Chronic; Antigen; Presentation; Compromises

In chronic infections T cell reponses significantly differ from the ones to acute infections because antigen presentation and inflammation persist. T cells show a largely dysfunctional response to antigen and become "exhausted." Since there is a paucity of studies on the role and functionality of CD4+ T cells in chronic infections, we have developed a mouse model for the side-by-side generation of memory and exhausted CD4+ T cells by reversible tetracycline-regulated antigen presentation in vivo. This system is quantitatively tunable and targeted to dendritic cells without potentially complicating innate, B cell and CD8+ T cell responses. Preliminary experiments showed that antigenspecific CD4+ T cells become dysfunctional quickly and can recover only some of their functions upon antigen removal. In this project we will first investigate the phenotype of the exhausted cells in comparison to memory cells. We will assess how a chronically persisting virus (MCMV) or the repeated application of immunostimulatory RNA oligonucleotides as a substitute for a virally induced inflammation may affect the phenotype and functionality of the cells. Second, we will analyze signal transduction in the exhausted cells. Our preliminary data already suggested that calcium signaling, unlike the MAP kinase pathway, is operational in exhausted cells, indicating that they were not anergized in the classical sense. Third, we will identify molecules differing between memory and exhausted cells by mRNA and miRNA microarray analyses.

在慢性感染中，T细胞反应与急性感染显著不同，因为抗原呈递和炎症持续存在。T细胞对抗原表现出很大程度上的功能失调反应，并变得“疲惫不堪”。“由于缺乏关于CD4+ T细胞在慢性感染中的作用和功能的研究，我们开发了一种小鼠模型，用于通过可逆的四环素调节的抗原呈递在体内并排产生记忆和耗尽的CD4+ T细胞。该系统是定量可调的，并且靶向树突细胞，而不会潜在地使先天性、B细胞和CD8+ T细胞应答复杂化。初步实验表明，抗原特异性CD4+ T细胞迅速变得功能失调，并且在抗原去除后只能恢复其部分功能。在这个项目中，我们将首先研究与记忆细胞相比，耗尽细胞的表型。我们将评估慢性持续病毒（MCMV）或免疫刺激性RNA寡核苷酸作为病毒诱导炎症的替代品的重复应用如何影响细胞的表型和功能。其次，我们将分析耗竭细胞中的信号转导。我们的初步数据已经表明，钙信号传导，不像MAP激酶途径，是在疲惫的细胞，这表明他们不是在经典意义上的无能量化。第三，我们将通过mRNA和miRNA微阵列分析来识别记忆细胞和耗竭细胞之间的差异分子。