How Chronic Antigen Presentation Compromises CD4+ T Cell Memory

慢性感染的T细胞反应与急性感染的T细胞反应明显不同，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的功能失调反应，并变得“筋疲力尽”。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，我们开发了一个小鼠模型，通过可逆性四环素调节的抗原呈递，在体内并排产生记忆和耗尽CD4+ T细胞。该系统是定量可调的，针对树突状细胞，没有潜在的复杂先天，B细胞和CD8+ T细胞反应。初步实验表明，抗原特异性CD4+ T细胞功能失调很快，抗原去除后只能恢复部分功能。在这个项目中，我们将首先研究耗尽细胞的表型与记忆细胞的比较。我们将评估慢性持续病毒（MCMV）或重复应用免疫刺激RNA寡核苷酸作为病毒诱导炎症的替代品如何影响细胞的表型和功能。其次，我们将分析衰竭细胞中的信号转导。我们的初步数据已经表明，与MAP激酶途径不同，钙信号在精疲力竭的细胞中是可操作的，这表明它们不是经典意义上的失能。第三，我们将通过mRNA和miRNA微阵列分析识别记忆细胞和衰竭细胞之间的分子差异。

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.