| 高 瑛,李 岚,张维华.Notch信号通路对急性B淋巴细胞白血病患者CD4+CD25+CD127dim/-调节性T细胞的调控作用[J].肿瘤学杂志,2022,28(1):46-52. |
| Notch信号通路对急性B淋巴细胞白血病患者CD4+CD25+CD127dim/-调节性T细胞的调控作用 |
| Modulatory Function of Notch Signaling Pathway to CD4+CD25+CD127dim/- Regulatory T Cells in Patients with B-cell Acute Lymphoblastic Leukemia |
| 投稿时间：2021-08-05 |
| DOI：10.11735/j.issn.1671-170X.2022.01.B009 |
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| 中文关键词: 急性淋巴细胞白血病 Notch信号通路 调节性T细胞 |
| 英文关键词:acute lymphoblastic leukemia Notch signaling pathway regulatory T cells |
| 基金项目:陕西省人民医院科技人才计划项目（2021BJ-26）；西安市科技计划项目 ［20YXYJ0009(11)］；陕西省卫生健康科研基金（2018A005） |
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| 中文摘要: |
| 摘 要：［目的］ 观察急性B淋巴细胞白血病（B-cell acute lymphoblastic leukemia，B-ALL）患者外周血Notch信号通路分子表达和CD4+CD25+CD127dim/-调节性T细胞（regulatory T cells，Treg）水平，评估Notch信号通路对B-ALL患者Treg活性的影响。 ［方法］ 入组31例B-ALL患者和20名对照者，分选血浆和外周血单个核细胞（peripheral blood mononuclear cells，PBMC），纯化CD4+CD25+CD127dim/- Treg。实时定量PCR法检测PBMC中Notch1~4、Hes1、Hes5 mRNA相对表达量，流式细胞术检测CD4+CD25+CD127dim/- Treg比例，酶联免疫吸附实验检测血浆白细胞介素10（interleukin-10，IL-10）和IL-35水平。使用Notch信号通路抑制剂GSI刺激B-ALL患者分选的PBMC，检测细胞增殖、Treg比例、IL-10和IL-35表达变化。使用GSI刺激B-ALL患者纯化的Treg，与自体PBMC以1∶10比例共培养，检测细胞增殖、IL-10、IL-35、干扰素-γ水平变化。两组间比较采用独立样本t检验或配对t检验。［结果］ B-ALL患者PBMC中Notch受体（包括Notch1、Notch2、Notch3、Notch4）和Notch下游信号分子Hes1、Hes5 mRNA相对表达量均较对照者升高（P<0.001）。B-ALL患者CD4+CD25+CD127dim/- Treg比例高于对照者（8.90%±2.41% vs 4.68%±1.01%，P<0.001）。B-ALL患者外周血IL-10和IL-35水平均高于对照者（P<0.05）。GSI刺激后B-ALL患者PBMC增殖水平与无GSI刺激组差异无统计学意义（P=0.689），但GSI刺激后Treg比例和IL-10、IL-35水平均较无GSI刺激组降低（P<0.05）。使用GSI刺激Treg后与自体PBMC共培养，其抑制PBMC增殖的能力减弱（P<0.001），IL-10和IL-35水平减少（P<0.05），但干扰素-γ水平增加（P<0.001）。［结论］ B-ALL患者外周血中Notch受体表达升高可能诱导CD4+CD25+CD127dim/- Treg数量增加和免疫抑制活性增强。 |
| 英文摘要: |
| Abstract：［Objective］ To investigate the effect of Notch signaling pathway on CD4+CD25+CD127dim/- regulatory T cell(Treg) levels in patients with B-cell acute lymphoblastic leukemia(B-ALL). ［Methods］ Thirty-one B-ALL patients and twenty healthy subjects(control group) were enrolled in the study. The peripheral blood mononuclear cells(PBMCs) were isolated and CD4+CD25+CD127dim/- Treg cells were sorted out. The relative expression levels of Notch 1~4， Hes1 and Hes5 mRNA in PBMCs were semi-quantified by RT-PCR. The percentage of CD4+CD25+CD127dim/- Treg was measured by flow cytometry. Plasma interleukin 10(IL-10) and IL-35 was measured by enzyme-linked immunosorbent assay. PBMCs from B-ALL patients were stimulated with Notch signaling inhibitor， then cell proliferation， Treg percentage， IL-10 and IL-35 secretion were investigated. Sorted Treg cells from B-ALL patients were stimulated with GSI， and then were co-cultured with autologous PBMC at the ratio of 1∶10， and cell proliferation， IL-10， IL-35 and interferon-γ expression levels were then assessed. Unpaired t test or paired t test was used for comparison between two groups. ［Results］ The relative mRNA expression levels of Notch receptors Notch1~4 and Notch signaling downstream molecules(Hes1 and Hes5) were elevated in PBMCs from B-ALL patients compared with in controls(P<0.001). The percentage of CD4+CD25+CD127dim/- Treg cells was increased in B-ALL patients compared with controls(8.90%±2.41% vs 4.68%±1.01%， P<0.001). Plasma IL-10 and IL-35 levels were up-regulated in B-ALL patients compared with in controls(P<0.05). There was no significant difference of cell proliferation between PBMCs with GSI stimulation and without GSI stimulation(P=0.689). However， GSI stimulation reduced Treg percentage as well as IL-10 and IL-35(P<0.05). The inhibitory function to PBMC proliferation was suppressed in response to GSI stimulation(P<0.001). GSI stimulation down-regulated IL-10 and IL-35(P<0.05)， while up-regulate interferon-γ expression in the supernatants(P<0.001). ［Conclusion］ Elevation of circulating Notch receptors in B-ALL patients might induce the increased number of CD4+CD25+CD127dim/- Treg cells and promote immunosuppressive activity. |
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