Deciphering the role of the IRF4 interactome in differentiating regulatory T and T helper 17 cells in health and autoimmune disease

解读 IRF4 相互作用组在区分健康和自身免疫性疾病中调节性 T 细胞和辅助性 T 细胞 17 中的作用

• 批准号: 408897752
• 负责人: Professor Dr. Tobias Bopp
• 金额: --
• 依托单位: Institut für Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/408897752?language=en
• 关键词: Deciphering; role; IRF4; interactome; differentiating

While T helper (Th) 17 cells have been implicated in the initiation and progression of autoimmune diseases, CD4+FOXP3+ regulatory T (Treg) cells have been shown to crucially contribute to the maintenance of peripheral tolerance by preventing these autoaggressive immune responses. It has been shown, that the transcription factor IRF4 plays a key role in Th17 and Treg cell lineage determination. The protein kinase CK2 is involved in the IRF4-steered regulation of gene transcription and CK2 activity essentially contributes to the delicate equilibrium between Th17 and Treg cells. Moreover, data indicate that IRF4 executes different tasks acting either as homodimer or in concert with different partners at certain stages during the course of T cell differentiation. However, there is still little knowledge about the underlying mechanisms and binding partners of IRF4 at distinct time points during the differentiation process. Further, it still remains elusive to which extent the events induced by IRF4 and its binding partners explain the pivotal role of this transcription factor in functionally opposed T cell subsets like Treg cells and Th17 cells.One of the major goals of the present grant application is to shed light on the impact of CK2 and IRF4 on Th17 and Treg cell lineage determination. Towards this purpose we will integrate time-resolved interactome, ChIPSeq, transcriptome and proteome analyses in the above-mentioned T cell subsets for the identification of CK2-dependent and CK2-independent IRF4 protein and DNA targets. The time-resolved multi"omics" dataset will be generated using Th17 and Treg cells generated ex vivo from transgenic reporter mice. The data resource created in the proposed project will allow us to pick candidate genes and proteins interacting with IRF4 and elucidate their impact on Th17 and Treg cell lineage determination in the preclinical model of multiple sclerosis, named experimental autoimmune encephalomyelitis (EAE).

虽然T辅助（Th）17细胞与自身免疫性疾病的起始和进展有关，但已显示CD4+FOXP3+调节性T（Treg）细胞通过防止这些自身攻击性免疫应答而对维持外周耐受性起关键作用。已经显示，转录因子IRF4在Th17和Treg细胞谱系确定中起关键作用。蛋白激酶CK2参与IRF4操纵的基因转录调节，CK2活性基本上有助于Th17和Treg细胞之间的微妙平衡。此外，数据表明，IRF4在T细胞分化过程中的某些阶段执行不同的任务，作为同源二聚体或与不同的伙伴合作。然而，在分化过程中的不同时间点，对IRF4的潜在机制和结合伴侣仍然知之甚少。此外，IRF4及其结合伴侣诱导的事件在何种程度上解释了这种转录因子在功能相反的T细胞亚群如Treg细胞和Th17细胞中的关键作用仍然是难以捉摸的。为此，我们将在上述T细胞亚群中整合时间分辨相互作用组、ChIPSeq、转录组和蛋白质组分析，以鉴定CK2依赖性和CK2非依赖性IRF4蛋白和DNA靶标。时间分辨的多“组学”数据集将使用从转基因报告小鼠离体产生的Th17和Treg细胞产生。在拟议的项目中创建的数据资源将使我们能够挑选与IRF4相互作用的候选基因和蛋白质，并阐明它们对多发性硬化症临床前模型（称为实验性自身免疫性脑脊髓炎（EAE））中Th17和Treg细胞谱系确定的影响。