Inhibiting mTORC1 pathway by rapamycin restores the balance of CD8+ T cell subsets and reduces CD8+ T cell-mediated platelet destruction in immune thrombocytopenia

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.