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）对于外周CD8+ T细胞向效应T细胞和CD4+ T细胞向不同th细胞亚群的分化至关重要。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。我们当前研究的主要目的是更好地理解控制记忆t细胞形成、持久性和功能的机制。该项目的基本假设是IRF4是记忆T细胞稳定性和th细胞亚群分化状态维持所必需的。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。在单核增生李斯特菌感染模型中，我们将研究IRF4在不同CD4+和CD8+记忆T细胞群中的表达水平，如效应记忆、中枢记忆和组织常驻记忆T细胞。在该感染模型中，将分析诱导Irf4缺失或强迫Irf4表达的小鼠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细胞分化状态稳定性的影响。我们将利用诱导Irf4缺失的CD4+ T细胞在鼠圆形线虫和啮齿柠檬酸杆菌的小鼠感染模型中进一步研究Irf4对TH2和TH17细胞稳定性的需求。最后，体外生成的IRF4缺陷记忆T细胞将被用来表征IRF4在基本细胞机制中的功能，如对生存细胞因子的反应或记忆T细胞的能量代谢。我们期望我们的结果将揭示IRF4在记忆t细胞形成和维持以及th细胞系稳定性中的功能。虽然我们的研究主要是为了阐明t细胞调节的基本机制，但结果可能会确定可以靶向调节感染，慢性炎症或自身免疫中的t细胞反应的调节途径。

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.