转录因子 IRF4 功能障碍影响原发性免疫性血小板减少症患者 Treg 细胞的免疫抑制功能。
Transcription Factor IRF4 Dysfunction Affects the Immunosuppressive Function of Treg Cells in Patients with Primary Immune Thrombocytopenia.
机构信息
Department of Hematology, Zhongshan Hospital Fudan University, Shanghai 200032, China.
Department of Hematology, Zhongshan Hospital Qinpu Branch, Fudan University, Shanghai 201700, China.
出版信息
Biomed Res Int. 2019 Jul 10;2019:1050285. doi: 10.1155/2019/1050285. eCollection 2019.
BACKGROUND
Th17/Treg balance skews towards Th17 in ITP patient. IRF4 has been highlighted for its close relationship to the immunosuppressive function of Treg cells and the IL-17 synthesis in CD4 T cells. This study was aimed at examining the effects of IRF4 to the Th17/Treg cells in patients with ITP.
METHODS
Treg and Teff cells were isolated from PBMCs of newly diagnosed ITP patients. The percentages of CD4CD25Foxp3Treg cells and the CD3CD4IL-17Th17 cells were detected by flow cytometry. After being cultured, the supernatants of Tregs were collected for IL-10 concentration test. The IRF4 levels of Tregs were measured. Teffs were cultured alone or with Tregs for 24 hours. Then the supernatants were collected for IL-17 concentration test. The binding intensity of IRF4 to the gene IL-10 in Treg cells was detected by ChIP-qPCR. Metabolic assays for Teffs and Tregs were performed with Agilent Seahorse XF96 Analyzer.
RESULTS
The secretion of IL-10 by Tregs was decreased in ITP patients. The intensity of IRF4 binding to IL-10 DNA of Tregs in patients was higher than that of normal controls and Teffs in ITP patients. The expressions of IRF4 of Tregs in ITP patients were remarkably lower than that of healthy controls. The percentage of Th17 cells in healthy controls was significantly increased after IRF4 mRNA silencing. Abnormal metabolism of Treg and Teff cells was found in ITP patients.
CONCLUSION
The skewed ratio of Th17/Treg cells and dysfunction of Treg cells in newly diagnosed ITP patients was at least partly caused by IRF4 dysfunction. The underlying mechanism might be the impact of IRF4 on the metabolism of Treg and Teff cells.
背景
特发性血小板减少性紫癜（ITP）患者中 Th17/Treg 平衡向 Th17 倾斜。IRF4 因其与 Treg 细胞的免疫抑制功能以及 CD4 T 细胞中 IL-17 的合成密切相关而备受关注。本研究旨在探讨 IRF4 对 ITP 患者 Th17/Treg 细胞的影响。
方法
从新诊断的 ITP 患者的 PBMC 中分离出 Treg 和 Teff 细胞。通过流式细胞术检测 CD4CD25Foxp3Treg 细胞和 CD3CD4IL-17Th17 细胞的百分比。培养后，收集 Treg 的上清液进行 IL-10 浓度检测。测量 Treg 的 IRF4 水平。Teffs 单独或与 Tregs 培养 24 小时后，收集上清液进行 IL-17 浓度检测。通过 ChIP-qPCR 检测 Treg 细胞中 IRF4 与基因 IL-10 的结合强度。使用安捷伦 Seahorse XF96 分析仪对 Teffs 和 Tregs 进行代谢测定。
结果
ITP 患者 Treg 细胞分泌的 IL-10 减少。患者 Tregs 中 IRF4 与 IL-10 DNA 的结合强度高于正常对照和 ITP 患者的 Teffs。ITP 患者 Tregs 的 IRF4 表达明显低于健康对照组。IRF4 mRNA 沉默后，健康对照组 Th17 细胞的百分比显著增加。ITP 患者 Treg 和 Teff 细胞的代谢异常。
结论
新诊断的 ITP 患者 Th17/Treg 细胞的偏倚比例和 Treg 细胞功能障碍至少部分是由 IRF4 功能障碍引起的。其潜在机制可能是 IRF4 对 Treg 和 Teff 细胞代谢的影响。
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