Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Shandong Key Laboratory of Immunohematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Front Immunol. 2021 Feb 17;12:630693. doi: 10.3389/fimmu.2021.630693. eCollection 2021.
Cytotoxic T lymphocytes (CTLs)-mediated platelet destruction plays an important role in the pathogenesis of primary immune thrombocytopenia (ITP). The programmed cell death protein 1 (PD-1) signaling can turn off autoreactive T cells and induce peripheral tolerance. Herein, we found that the expression of PD-1 and its ligand PD-L1 on CD8 T cells from ITP patients was decreased. Activating PD-1 pathway by PD-L1-Fc fusion protein inhibited CTLs-mediated platelet destruction in ITP . PD-1 promoter hypermethylation in CD8 T cells was found in ITP patients, resulting in decreased PD-1 expression. The demethylating agent decitabine at a low dose was proved to restore the methylation level and expression of PD-1 on CD8 T cells and reduce the cytotoxicity of CTLs of ITP patients. The phosphorylation levels of phosphatidylinositol 3-kinase (PI3K) and AKT in CD8 T cells were significantly downregulated by low-dose decitabine. Furthermore, blocking PD-1 could counteract the effect of low-dose decitabine on CTLs from ITP patients. Therefore, our data suggest that the aberrant PD-1/PD-L1 pathway is involved in the pathophysiology of ITP and enhancing PD-1/PD-L1 signaling is a promising therapeutic approach for ITP management. Our results reveal the immunomodulatory mechanism of low-dose decitabine in ITP by inhibiting CTLs cytotoxicity to autologous platelets through PD-1 pathway.
细胞毒性 T 淋巴细胞 (CTLs)介导的血小板破坏在原发性免疫性血小板减少症 (ITP) 的发病机制中起着重要作用。程序性细胞死亡蛋白 1 (PD-1) 信号可以关闭自身反应性 T 细胞并诱导外周耐受。在此，我们发现 ITP 患者 CD8 T 细胞上的 PD-1 及其配体 PD-L1 的表达减少。PD-L1-Fc 融合蛋白激活 PD-1 通路可抑制 ITP 中 CTLs 介导的血小板破坏。在 ITP 患者中发现 CD8 T 细胞中的 PD-1 启动子发生高甲基化，导致 PD-1 表达减少。低剂量地西他滨被证明可以恢复 CD8 T 细胞中 PD-1 的甲基化水平和表达，并降低 ITP 患者 CTLs 的细胞毒性。低剂量地西他滨可显著下调 CD8 T 细胞中磷脂酰肌醇 3-激酶 (PI3K) 和 AKT 的磷酸化水平。此外，阻断 PD-1 可拮抗低剂量地西他滨对 ITP 患者 CTLs 的作用。因此，我们的数据表明，异常的 PD-1/PD-L1 通路参与了 ITP 的病理生理学，增强 PD-1/PD-L1 信号是 ITP 管理的一种有前途的治疗方法。我们的结果通过抑制 CTLs 对自身血小板的细胞毒性，通过 PD-1 通路揭示了低剂量地西他滨在 ITP 中的免疫调节机制。
