Thrombosis research · 2025
Inhibiting mTORC1 pathway by rapamycin restores the balance of CD8+ T cell subsets and reduces CD8+ T cell-mediated platelet destruction in immune thrombocytopenia.
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Ni Xiaofei, Guo Jinghan, Zhu Xiaojing, Wang Haoyi, Wang Lingjun, Zhao Yajing, Yu Tianshu, Han Shouqing, Li Yubin, Zhou Hai, Hou Ming, Qiu Jihua
Аннотация
BACKGROUND: CD8+ T cells contribute to platelet destruction in immune thrombocytopenia (ITP). Rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor, has demonstrated efficacy in relapsed/refractory ITP. However, its impact on CD8+ T cells in ITP remains unexplored.
METHODS: Gene expression profiles from GSE43177 dataset were analyzed using gene set enrichment analysis (GSEA). Activation of the mTORC1 pathway and CD8+ T cell subsets was evaluated using flow cytometry. CD8+ T cell cytotoxicity was assessed by measuring perforin, granzyme B expression and platelet apoptosis. Additionally, an active ITP murine model was established for validation.
RESULTS: GSEA of the GSE43177 dataset revealed significant enrichment of mTOR pathway in ITP patients with high CD8+ T cell abundance. CD8+ T cells from peripheral blood of ITP patients exhibited enhanced mTORC1 pathway activation, as evidenced by elevated phosphorylation levels of mTOR, p70S6K, and 4EBP1. Additionally, CD8+ T cell subsets were imbalanced in ITP patients, with reduced naïve T cells, increased effector memory T cells, and decreased CD28- T cells, alongside elevated cytotoxicity. In vitro treatment with rapamycin restored the homeostasis of CD8+ T cell subsets and reduced CD8+ T cell-mediated platelet apoptosis. Furthermore, rapamycin effectively ameliorated thrombocytopenia and modulated CD8+ T cell subsets in the active ITP murine model.
CONCLUSION: Our findings demonstrate that inhibition of mTORC1 by rapamycin restores the homeostasis of CD8+ T cell subsets and reduces CD8+ T cell-mediated platelet destruction in ITP. These results provide a mechanistic rationale for the clinical application of rapamycin in ITP management.
METHODS: Gene expression profiles from GSE43177 dataset were analyzed using gene set enrichment analysis (GSEA). Activation of the mTORC1 pathway and CD8+ T cell subsets was evaluated using flow cytometry. CD8+ T cell cytotoxicity was assessed by measuring perforin, granzyme B expression and platelet apoptosis. Additionally, an active ITP murine model was established for validation.
RESULTS: GSEA of the GSE43177 dataset revealed significant enrichment of mTOR pathway in ITP patients with high CD8+ T cell abundance. CD8+ T cells from peripheral blood of ITP patients exhibited enhanced mTORC1 pathway activation, as evidenced by elevated phosphorylation levels of mTOR, p70S6K, and 4EBP1. Additionally, CD8+ T cell subsets were imbalanced in ITP patients, with reduced naïve T cells, increased effector memory T cells, and decreased CD28- T cells, alongside elevated cytotoxicity. In vitro treatment with rapamycin restored the homeostasis of CD8+ T cell subsets and reduced CD8+ T cell-mediated platelet apoptosis. Furthermore, rapamycin effectively ameliorated thrombocytopenia and modulated CD8+ T cell subsets in the active ITP murine model.
CONCLUSION: Our findings demonstrate that inhibition of mTORC1 by rapamycin restores the homeostasis of CD8+ T cell subsets and reduces CD8+ T cell-mediated platelet destruction in ITP. These results provide a mechanistic rationale for the clinical application of rapamycin in ITP management.