期刊
FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.630693
关键词
immune thrombocytopenia; decitabine; cytotoxic T lymphocytes; PD-1; PD-L1
类别
资金
- National Natural Science Foundation of China [82070122, 81973994, 81900121, 81770133, 81770114]
- Major Research Plan of National Natural Science Foundation of China [91942306]
- Major Research Plan of Shandong Province [2019GSF108240]
- State Key Clinical Specialty of China for Hematological Disease
- Shandong Provincial Clinical Medicine Research Center for Hematology
- Branch of National Clinical Research Center for Hematology
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. Low-dose decitabine inhibits CTLs cytotoxicity to autologous platelets through the PD-1 pathway in ITP.
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.
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