Promoter methylation and increased expression of PD-L1 in patients with active tuberculosis.

IF 4.1 3区 生物学 Q2 CELL BIOLOGY Microbial Cell Pub Date : 2024-07-29 eCollection Date: 2024-01-01 DOI:10.15698/mic2024.07.832
Yen-Han Tseng, Sheng-Wei Pan, Jhong-Ru Huang, Chang-Ching Lee, Jung-Jyh Hung, Po-Kuei Hsu, Nien-Jung Chen, Wei-Juin Su, Yuh-Min Chen, Jia-Yih Feng
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Abstract

The PD-1/PD-L1 pathway plays a pivotal role in T cell activity and is involved in the pathophysiology of Mycobacterium tuberculosis (MTB) infection. DNA methylation is a mechanism that modulates PD-L1 expression in cancer cells. However, its effect on PD-L1 expression in macrophages after MTB infection remains unknown. We prospectively enrolled patients with active tuberculosis (TB) and non-TB subjects. The expression of PD-L1 and methylation-related genes in peripheral blood mononuclear cells (PBMCs) were investigated and their correlation with disease severity and treatment outcomes were examined. PD-L1 promoter methylation status was evaluated using bisulfite sequencing. Immunohistochemistry (IHC) and immunofluorescence (IF) staining were used to visualize PD-L1- and TET-1-expressing cells in lung tissues from patients with TB and in macrophage cell lines with MTB-related stimulation. In total, 80 patients with active TB and 40 non-TB subjects were enrolled in the analysis. Patients with active TB had significantly higher expression of PD-L1, DNMT3b, TET1, TET2, and lower expression of DNMT1, compared to that in the non-TB subjects. The expression of PD-L1 and TET-1 was significantly associated with 1-month smear and culture non-conversion. IHC and IF staining demonstrated the co-localization of PD-L1- and TET-1-expressing macrophages in patients with pulmonary TB and in human macrophage cell lines after MTB-related stimulation. DNMT inhibition and TET-1 knockdown in human macrophages increased and decreased PD-L1 expression, respectively. Overall, PD-L1 expression is increased in patients with active TB and is correlated with treatment outcomes. DNA methylation is involved in modulating PD-L1 expression in human macrophages.

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活动性肺结核患者的启动子甲基化和 PD-L1 表达增加。
PD-1/PD-L1 通路在 T 细胞活性中起着关键作用,并参与结核分枝杆菌(MTB)感染的病理生理学。DNA 甲基化是调节癌细胞中 PD-L1 表达的一种机制。然而,DNA甲基化对MTB感染后巨噬细胞中PD-L1表达的影响仍然未知。我们前瞻性地招募了活动性肺结核(TB)患者和非肺结核受试者。我们调查了外周血单核细胞(PBMCs)中 PD-L1 和甲基化相关基因的表达,并研究了它们与疾病严重程度和治疗结果的相关性。采用亚硫酸氢盐测序法评估了 PD-L1 启动子甲基化状态。免疫组化(IHC)和免疫荧光(IF)染色用于观察肺结核患者肺组织和受 MTB 相关刺激的巨噬细胞系中表达 PD-L1 和 TET-1 的细胞。共有 80 名活动性肺结核患者和 40 名非肺结核患者参与了分析。与非肺结核受试者相比,活动性肺结核患者的 PD-L1、DNMT3b、TET1 和 TET2 的表达明显较高,而 DNMT1 的表达较低。PD-L1 和 TET-1 的表达与 1 个月涂片和培养未转阴有明显相关性。IHC 和 IF 染色显示,在肺结核患者体内和经 MTB 相关刺激后的人类巨噬细胞系中,PD-L1 和 TET-1 表达的巨噬细胞共定位。人类巨噬细胞中的 DNMT 抑制和 TET-1 敲除分别增加和减少了 PD-L1 的表达。总体而言,活动性肺结核患者的 PD-L1 表达增加,并与治疗效果相关。DNA 甲基化参与调节人类巨噬细胞中 PD-L1 的表达。
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来源期刊
Microbial Cell
Microbial Cell Multiple-
CiteScore
6.40
自引率
0.00%
发文量
32
审稿时长
12 weeks
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