Abstract
Transplant rejection, primarily caused by the immune system's recognition of allografts, continues to pose a significant challenge to graft survival. Drawing inspiration from the function of interferon regulatory factor 2 (IRF2) in tumour immune evasion, we explored its potential role in the context of transplantation. We quantified the expression of MHC-I, PD-L1 and associated molecules in cardiac tissues of IRF2 KO mice through RNA and protein analyses. Subsequently, we established a murine heterotopic cardiac transplantation model using IRF2-KO donors to evaluate the role of IRF2 in post-transplant survival. Immunofluorescence and immunohistochemical staining revealed IRF2-dependent regulation of MHC-I and PD-L1 in grafts, accompanied by altered CD4+/CD8+T-cell infiltration patterns. Further, in vitro experiments employing RNA interference (RNAi) in cardiomyocytes demonstrated IRF2-mediated control of MHC-I/PD-L1 expression and its functional impact on T-cell proliferation and apoptosis in co-culture systems. In mice heart tissues, as revealed by the transcriptome sequencing, IRF2 knockdown downregulated immune-related pathways (MHC, inflammation) and upregulated apoptosis-linked pathways. IRF2 deficiency enhances PD-L1 and suppresses TAP2/ERAP1-MHC-I axis at RNA and protein levels. After transplantation, IRF2 deficiency in allografts prolongs survival by attenuating CD4+/CD8+T-cell infiltration via PD-L1 upregulation and MHC-I downregulation, thereby mitigating inflammatory injury. In vitro, IRF2 knockdown in HL-1 murine cardiomyocytes via siRNA upregulated PD-L1 expression, suppressed TAP2/ERAP1 levels and attenuated T-cell proliferation while promoting apoptosis in co-culture systems. We elucidate the principal mechanism underlying IRF2-mediated allograft immune evasion, thereby identifying its targeted modulation as an innovative therapeutic approach to prevent early acute rejection and diminish long-term reliance on immunosuppressive therapy in transplantation.