The role of Interferon Regulatory Factor 4 in the regulation of T-cell memory

转录因子干扰素调节因子4(IRF4)在外周CD8+T细胞分化为效应性T细胞和CD4+T细胞分化为不同的TH细胞亚群过程中起重要作用。有进一步的证据表明，IRF4表达的大小和动力学决定了T细胞成熟的命运。我们目前研究的主要目的是更好地了解控制记忆T细胞形成、持续和功能的机制。该项目的基本假设是，IRF4对于记忆T细胞的稳定性和维持TH细胞亚群的分化状态是必需的。为了验证这一假设，我们计划应用体外研究和小鼠感染模型。在单核细胞增多性李斯特氏菌感染模型中，我们将研究IRF4在不同的CD4+和CD8+记忆T细胞群中的表达水平，例如效应器记忆T细胞、中央记忆T细胞和组织驻留记忆T细胞。在这种感染模型中，将分析来自IRF4可诱导缺失或强制表达的小鼠的T细胞，以确定IRF4对CD4+和CD8+记忆细胞亚群的持久性和功能以及对CD4+TH1-细胞分化状态的稳定性的影响。在拉蒂类圆线虫和轮状柠檬酸杆菌的小鼠感染模型中，使用具有可诱导的IRF4缺失的CD4+T细胞，我们将进一步分别研究IRF4对TH2和TH17细胞稳定性的要求。最后，在体外产生的IRF4缺陷的记忆T细胞将被用来表征IRF4在基本细胞机制上的功能，例如对记忆T细胞中存活细胞因子或能量代谢的反应。我们期望我们的结果将揭示IRF4在记忆性T细胞的形成和维持以及TH细胞谱系的稳定中的作用。虽然我们的研究主要是为了阐明T细胞调节的基本机制，但结果可能确定可以靶向调节T细胞在感染、慢性炎症或自身免疫中的反应的调节途径。

The transcription factor Interferon Regulatory Factor 4 (IRF4) is essential for the differentiation of peripheral CD8+ T cells to effector T cells and of CD4+ T cells to different TH-cell subsets. There is further evidence that magnitude and kinetics of IRF4 expression determine the fate of T-cell maturation. The main aim of our current study is a better understanding of the mechanisms controlling memory T-cell formation, persistence and function. The underlying hypothesis of the project is that IRF4 is required for the stability of memory T cells and for the maintenance of the differentiation status of TH-cell subsets. To test this hypothesis, we plan to apply in vitro studies and mouse infection models. In the Listeria monocytogenes infection model, we will investigate IRF4 expression levels in different CD4+ and CD8+ memory T-cell populations, e.g. effector memory, central memory and tissue resident memory T cells. T cells from mice with inducible Irf4 deletion or with forced Irf4 expression will be analysed in this infection model to determine the impact of IRF4 on the persistence and function of CD4+ and CD8+ memory cell subsets and on the stability of the CD4+ TH1-cell differentiation status. Using CD4+ T cells with inducible Irf4 deletion in mouse infection models for Strongyloides ratti and for Citrobacter rodentium, we will further examine the IRF4 requirement for the stability of TH2 and TH17 cells, respectively. Finally, in vitro-generated Irf4-deficient memory T cells will be utilized to characterize the function of IRF4 on fundamental cellular mechanisms, such as the response to survival cytokines or energy metabolism in memory T cells. We expect that our results will reveal the function of IRF4 in memory T-cell formation and maintenance, and in stability of TH-cell lineages. Although our study mainly aims at clarifying fundamental mechanisms of T-cell regulation, results might identify regulatory pathways that can be targeted to modulate T-cell responses in infection, chronic inflammation or autoimmunity.