Abstract
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 in vitro. 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.
Highlights
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by immune-mediated platelet destruction and impaired platelet production [1,2,3,4]
Previous studies have shown that PD-1 and PD-L1 expression on peripheral blood mononuclear cells (PBMCs) and CD4+ T cells were lower in ITP patients [15, 16]
In vitro studies have proved that PD-L1-Fc recombinant fusion protein (PD-L1Fc, linking the extracellular domains of PD-1) increased T cell apoptosis and inhibited the activation and proliferation of T cells in ITP, suggesting the important role of PD-1 pathway in the pathogenesis of ITP [17]
Summary
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by immune-mediated platelet destruction and impaired platelet production [1,2,3,4]. In addition to platelet autoantibodies, abnormal T cell immunity, especially CD8+ cytotoxic T lymphocytes (CTLs) play a vital role in the pathogenesis of ITP [5,6,7,8]. CTLs have been demonstrated to cause direct platelet lysis in patients with active ITP [9]. Previous studies have shown that PD-1 and PD-L1 expression on peripheral blood mononuclear cells (PBMCs) and CD4+ T cells were lower in ITP patients [15, 16]. In vitro studies have proved that PD-L1-Fc recombinant fusion protein (PD-L1Fc, linking the extracellular domains of PD-1) increased T cell apoptosis and inhibited the activation and proliferation of T cells in ITP, suggesting the important role of PD-1 pathway in the pathogenesis of ITP [17]
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