International immunopharmacology · 2025
Idelalisib modulates CD4+ T cell responses to mitigate rejection of allografts in mice.
СтатьяНазвание и аннотация: Перевод в очереди
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Zhang Weiqi, Zhang Xiaohan, Hu Lu, Jin Shuai, Pitts Leonard, Kofler Markus, Wang Zhihong, Iske Jasper, Nian Yeqi, Shen Zhongyang
Аннотация
BACKGROUND: Immune rejection remains a leading cause of graft loss following organ transplantation, with CD4+ T cells playing a central role in this process. The PI3K/AKT/mTOR signaling pathway is essential for the activation, proliferation, and metabolic reprogramming of CD4+ T cells, making it an attractive therapeutic target. However, the role of Idelalisib (ID), a selective PI3Kδ inhibitor, in transplant immunity remains underexplored.
METHODS: Purified CD4+ T cells from the spleens of C57BL/6 mice were cultured with ID. Activation, proliferation, differentiation and survival were evaluated. A fully mismatched skin and heart transplantation model was used to assess ID's effects on rejection. Histopathology analysis and transcriptomic sequencing were performed.
RESULTS: ID significantly suppressed CD4+ T cell activation, proliferation, and Th1 differentiation, while enhancing cell survival-contrasting with the pro-apoptotic effects observed with the mTOR inhibitor rapamycin (Rapa). In the skin and heart transplantation models, ID reduced acute rejection, extended graft survival, and decreased the proliferation of CD4+ T cells and B cells. Transcriptomic analysis revealed downregulation of genes involved in T cells activation and differentiation (e.g., Zap70, Stat4), as well as markers of glycolysis (e.g., Gapdh, Pfkm). Functional assays confirmed reduced glucose uptake and lactate production in ID-treated cells.
CONCLUSIONS: ID uniquely modulates T cell responses through PI3Kδ inhibition, providing a distinct immunosuppressive mechanism from that of mTOR inhibitors. These findings highlight the therapeutic potential of ID in preventing transplant rejection and reveal a critical link between PI3K signaling and CD4+ T cell metabolism.
METHODS: Purified CD4+ T cells from the spleens of C57BL/6 mice were cultured with ID. Activation, proliferation, differentiation and survival were evaluated. A fully mismatched skin and heart transplantation model was used to assess ID's effects on rejection. Histopathology analysis and transcriptomic sequencing were performed.
RESULTS: ID significantly suppressed CD4+ T cell activation, proliferation, and Th1 differentiation, while enhancing cell survival-contrasting with the pro-apoptotic effects observed with the mTOR inhibitor rapamycin (Rapa). In the skin and heart transplantation models, ID reduced acute rejection, extended graft survival, and decreased the proliferation of CD4+ T cells and B cells. Transcriptomic analysis revealed downregulation of genes involved in T cells activation and differentiation (e.g., Zap70, Stat4), as well as markers of glycolysis (e.g., Gapdh, Pfkm). Functional assays confirmed reduced glucose uptake and lactate production in ID-treated cells.
CONCLUSIONS: ID uniquely modulates T cell responses through PI3Kδ inhibition, providing a distinct immunosuppressive mechanism from that of mTOR inhibitors. These findings highlight the therapeutic potential of ID in preventing transplant rejection and reveal a critical link between PI3K signaling and CD4+ T cell metabolism.