Mechanisms of CD4+ T Cell Exhaustion by Persistent Antigen and Chronic Inflammation

肺结核、疟疾和艾滋病毒/艾滋病等慢性感染是全球卫生面临的主要挑战。在这些疾病和癌症中，免疫系统无法清除随后持续存在的致病因子。在这种情况下，T细胞由于持续的抗原呈递、炎症和使人衰弱的微环境而变得功能失调，这一过程概括地称为衰竭。在研究体内可调节抗原表达的小鼠模型中CD 4 + T辅助细胞耗竭的研究中，我们已经确定了细胞如何被以不同剂量和不同时间段呈递的抗原耗竭。在这里，我们想解决我们已经确定的某些基因如何影响T辅助细胞耗竭：转录因子（Helios），两对parabyte转录因子（Tox和Tox 2，Egr 2和3）和一对MAP激酶抑制剂（Spry 1和2）可能会影响T辅助细胞耗竭。使用主要loxP侧翼的基因座和诱导型Cre重组酶，我们将在暴露于不同水平的持续抗原的细胞中的耗竭阶段特异性地删除基因。我们希望细胞表现出更少的衰竭表型。我们将进一步分析受缺失影响的靶基因和染色质变化，以找到可以被药物干扰的耗竭机制，以支持对慢性感染和癌症的免疫反应。此外，我们还将研究急性和慢性炎症对三种不同类型LCM病毒感染的T细胞耗竭的作用。

Chronic infections like tuberculosis, malaria and HIV/AIDS are major challenges to global health. In such diseases, and in cancer, the immune system cannot clear the causing agent which then persists. Under such circumstances T cells become dysfunctional due to continued antigen presentation, inflammation, and debilitating microenvironments, a process summarily called exhaustion. In studies investigating CD4+ T helper cell exhaustion in a mouse model of regulatable antigen expression in vivo we have defined how the cells become exhausted by antigen presented at different doses and for different periods of time. Here we want to address how certain genes we have identified affect T helper cell exhaustion: A transcription factor (Helios), two pairs of paralog transcription factors (Tox and Tox2, Egr2 and 3) and a pair of MAP kinase inhibitors (Spry1 and 2) are likely to affect T helper cell exhaustion. Using mostly loxP flanked loci and an inducible Cre recombinase we will delete the genes specifically in the phase of exhaustion in cells exposed to different levels of persisting antigen. We expect the cells to exhibit a less exhausted phenotype. We will further analyse the target genes and chromatin changes affected by the deletions to find mechanisms of exhaustion that can be pharmaceutically interfered with to support immune responses to chronic infections and cancer. In addition we will investigate the role of acute and chronic inflammation for T cell exhaustion by three different kinds of infections with the LCM virus.