Idelalisib modulates CD4+ T cell responses to mitigate rejection of allografts in mice

  • Int Immunopharmacol. 2025 Sep 23:162:115155. doi: 10.1016/j.intimp.2025.115155.
Weiqi Zhang  1 ,  Xiaohan Zhang  1 ,  Lu Hu  2 ,  Shuai Jin  2 ,  Leonard Pitts  3 ,  Markus Kofler  3 ,  Zhihong Wang  4 ,  Jasper Iske  5 ,  Yeqi Nian  6 ,  Zhongyang Shen  7
Affiliations
  • 1. Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China; Department of Kidney Transplant, Tianjin First Central Hospital, Tianjin, China.
  • 2. Department of Kidney Transplant, Tianjin First Central Hospital, Tianjin, China; Tianjin Medical University First Central Clinical College, Tianjin, China.
  • 3. Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353 Berlin, Germany.
  • 4. Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China.
  • 5. Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), 13353 Berlin, Germany; Berlin Institute of Health, 10117 Berlin, Germany. Electronic address: [email protected].
  • 6. Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China; Department of Kidney Transplant, Tianjin First Central Hospital, Tianjin, China. Electronic address: [email protected].
  • 7. Research Institute of Transplant Medicine, School of Medicine, Nankai University, Tianjin, China; Department of Kidney Transplant, Tianjin First Central Hospital, Tianjin, China. Electronic address: [email protected].
PMID: 40602262 DOI: 10.1016/j.intimp.2025.115155
Abstract

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.

Keywords
Alloimmune response; CD4(+) T cells; Idelalisib; Transplant rejection.
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