Idelalisib Modulates CD4+ T Cell Responses to Mitigate Rejection of Allografts in Mice

Immune rejection remains a major 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 critical for CD4+ T cells activation, proliferation, and metabolic reprogramming, making it a promising therapeutic target. The role of Idelalisib (ID), a selective PI3Kδ inhibitor, in transplant immunity remains underexplored. Here, we demonstrated ID significantly suppressed CD4+ T cells activation, proliferation, and Th1 differentiation while enhancing cell survival. In the skin and heart transplantation model, ID attenuated acute rejection, prolonged graft survival, and reduced CD4+ T cells and B cells proliferation. Transcriptomics revealed downregulation of T cells activation and differentiation genes and glycolysis marker. Functional assays confirmed impaired glucose uptake and lactate production in ID-treated cells. Conclusions. ID uniquely modulates T cells responses via PI3Kδ inhibition, offering a distinct immunosuppressive mechanism compared to mTOR inhibitors. Taken together, our data highlight ID’s potential as a therapeutic agent for mitigating transplant rejection and elucidates the interplay between PI3K signaling and CD4+ T cells metabolism.